bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy against tau pathology in mouse models requires cytosolic Fc receptor TRIM21
Authors: McEwan Will
Published: December 2023

Background

The passive transfer of monoclonal antibodies reduces tau pathology in mouse models and is under evaluation as a potential immunotherapeutic strategy against Alzheimer’s disease and other tauopathies. The mechanisms that drive therapeutic protection of anti‐tau antibodies are not well understood.

Method

P301S tau transgenic animals were treated with antibodies against pS422 and analysed for tau pathology by biochemical fractionation. Organotypic hippocampal slice cultures were used as a model of tau seeding and neutralisation. AAV serotypes were used to deliver tau‐selective degraders.

Result

Genetic deletion of the cytosolic antibody receptor and E3 ubiquitin ligase TRIM21 rendered tau immunotherapy ineffective in animal models. In organotypic slices, expression of TRIM21 was essential for protection against seeded aggregation of tau. Cytosolic antibody‐tau complexes were visible inside neurons in complex with TRIM21 shortly after application of tau assemblies and antibodies to the cell exterior. Nanobody‐based degraders were developed using TRIM21 and found to protect against tau pathology.

Conclusion

Anti‐tau antibodies can engage extracellular tau seeds and enter neurons as a complex. Following cytosolic entry, TRIM21 engages the antibodies and mediates neutralisation of tau seeding activity. The results reveal a mechanism that can be optimised for future immunotherapeutics. In this direction, AAV‐delivered degraders reveal a route by which tau aggregates may be selectively removed from the brain.
Supporting Carer Partners of People with Dementia: A Study from Six Countries
Authors: Kinchin Irina , Adrion Emily R , Chen Yaohua Sophie , Dupont Charlèss , Mayan Inbal , Epenge Emmanuel , Almirall‐Sanchez Arianna ,   Economics of Dementia and Brain Health Special Interest Group at the Global Brain Health Institute
Published: December 2023

Background

Dementia not only affects the person diagnosed, but also their family and wider support network. Care partners are often unpaid and untrained. They face financial, social, and psychological stressors that impact their health and wellbeing and may ultimately affect the quality of care. Easy and timely access to information, training, services, social and financial support throughout a caring trajectory are vital elements of a holistic support system. This study aims to assess dementia‐specific support and services in different countries and healthcare settings and map those against the needs of care partners.

Methods

An exploratory analysis of publicly available information on dementia‐specific support and services in six countries conveniently sampled, including Belgium, the Democratic Republic of Congo, France, Ireland, Israel, and the UK. A descriptive analysis of the data was performed by the number and type of services, sector, and accessibility. Support and services were subsequently mapped against the taxonomy of needs of care partners of people with dementia identified from the literature.

Results

Preliminary results revealed that all selected countries except the Democratic Republic of Congo exhibited publicly accessible information on dementia‐specific support and services available in the capital, main cities, and rural areas. The public and NGO were the most prevalent sector providing the support. Depth, detail, and location of information on available services varied across countries, in some instances requiring visits to multiple governmental, public sector or quasi‐public sector sites. Final results will be presented at AAIC 2023.

Conclusion

Unmet needs are not just an individual issue, but a phenomenon linked to social and economic disadvantage and societal inequality. The creation and implementation of means to deliver multisectoral care, support and services for carer partners of people with dementia to meet their unique needs and prevent a decline in physical and mental health and social wellbeing is warranted irrespective of the healthcare setting, but particularly so in low‐ and middle‐income settings.
The effectiveness of the glucagon‐like peptide 1 receptor agonist in improving cognitive function
Authors: Rasmussen Naoise , Burns Richéal , Coughlan Karen
Published: December 2023

Background

Recent evidence suggests that glucagon‐like peptide 1 receptor agonists, commonly used to treat diabetes and obesity (Norgaard, 2022), are neuroprotective (Cheng, 2022), which may result in an improvement in cognitive function (Norgaard, 2022). The aim of this review is to determine the potential effectiveness of glucagon‐like peptide 1 receptor agonist therapy at improving cognitive function in a human population in literature published thus far.

Method

Searches for applicable studies were conducted on PubMed, Cochrane library, Google scholar, CINAHL and Clinical Trials.gov. Studies which compare the efficacy of the glucagon‐like peptide 1 receptor agonist to placebo were included. The main outcome is the change in cognitive function assessed via cognitive testing. Data was expressed as mean difference/hazard ratio and corresponding 95% confidence interval. Quality assessment was conducted with the Cochrane risk of bias tool for randomized trials (RoB 2). Heterogeneity was assessed with the chi‐squared test and I2 statistic. The study was registered on PROSPERO (ID: CRD42022366254).

Result

A total of n = 11,424 studies were identified for this review. After the removal of duplicates and the application of eligibility criteria, five studies (comprising n = 8,950 individuals) were included. Risk of bias across the included studies was low. Only one study reported an improvement in cognitive function associated with glucagon‐like peptide 1 receptor agonists. The results of the meta‐analysis inclusive of the five studies are inconclusive.

Conclusion

Overall, four of the five included studies were hampered by short drug duration times and small population sizes, which may have impacted the final result and conclusion. There is an urgent need for therapies to improve cognitive function, due to the rapid rise in cognitive decline worldwide. Glucagon‐like peptide 1 receptor agonists may fill this need, although further research is warranted.

Cheng. (2022). The Role of Glucagon‐Like Peptide‐1 Receptor Agonists (GLP‐1 RA) in Diabetes‐Related Neurodegenerative Diseases. Drug Des Devel Ther, 16: 665‐684.

Norgaard. (2022). Treatment with glucagon‐like peptide‐1 receptor agonists and incidence of dementia: Data from pooled double‐blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N.Y), 8(1):e12268.
In vivo safety and efficacy of a CRISPR‐based gene therapy for Alzheimer’s disease
Authors: Aulston Brent D , Branes Kristen , Checka Nidhi , Parra‐Rivas Leonardo A , Roy Subhojit
Published: December 2023

Background

Our lab has developed a gene‐editing strategy to target the extreme C‐terminus (C‐term) of APP (amyloid precursor protein) – a gene with a central and indisputable role in AD. In physiologic states, the APP protein is cleaved by α‐secretases to generate neuroprotective sAPPα; but in AD (both sporadic and familial), the alternative β‐cleavage pathway is active, generating pathologic fragments (including Aβ). Specifically, our approach attenuates pathologic β‐cleavage products by disrupting a pentapeptide “YENPTY” domain at the APP C‐term, and this retains the edited APP (APP‐ΔC) at the cell‐surface, augmenting neuroprotective and neuroregenerative α‐cleavage.

Method

In order to assess the safety and efficacy of our approach in vivo, we used two different CRISPR‐editing approaches. First, we generated germline edits in Wt and APP knockin (APPNL‐G‐F) mice by injecting embryos with APP C‐term targeting CRISPRs. We then selected founders to produce stable strains of WT and APP‐KI in which the APP C‐term was genomically deleted (referred to as WtΔC and KI‐ΔC mice respectively). In another set of experiments, we packaged APP C‐term CRISPRs into AAV vectors and systemically injected AAVs into APP‐KI mice.

Result

WtΔC showed no cognitive deficits or histological abnormalities compared to Wt controls. KI‐ΔC showed a dramatic reduction of amyloid beta plaques and associated neuroinflammatory markers and similar results were observed in AAV‐treated KI mice. Moreover, both germline and somatic APP C‐term editing produced an increase in neuroprotective sAPPα.

Conclusion

In total, these data demonstrate that our approach is safe and efficacious in vivo and validate the feasibility of our APP C‐terminus editing approach as a therapeutic for AD.
The association between diabetes measures and Alzheimer’s disease biomarkers in CSF – A meta‐analysis
Authors: van Gils Veerle , Rizzo Marianna , Côte Jade , Viechtbauer Wolfgang , Visser Pieter Jelle , Jansen Willemijn J. , Vos Stephanie J. B. ,   the PRIME consortium
Published: December 2023

Background

Diabetes and blood glucose markers have previously been linked to cognitive decline. However, findings on the relation of diabetes with underlying Alzheimer’s disease (AD) biomarkers are inconclusive. We aimed to explore whether diabetes and blood glucose markers are associated with AD biomarkers in cerebrospinal fluid (CSF) by performing a meta‐analysis of existing studies.

Method

A systematic search in PubMed and Embase with abstract and full‐text screening resulted in the inclusion of 13 studies with 5,052 participants in our meta‐analysis. We included studies that provided results on the association between a diabetes measure and an AD biomarker in CSF (Table 1). Diabetes measures included diabetes diagnosis or glucose measures, i.e. fasting blood glucose, HbA1c, or insulin resistance index. AD biomarkers included CSF amyloid‐beta42, p‐tau and/or t‐tau. Where needed, results were converted to partial or biserial correlation coefficients. We performed a random effects meta‐analysis on the correlation coefficients per CSF biomarker, using the DerSimonian and Laird procedure and Knapp‐Hartung method. Meta‐regression was used to test potential moderating effects of age, sex, setting (memory clinic or population), % dementia cases, correlation type (Pearson, partial, or biserial), diabetes measure (diabetes diagnosis or glucose marker), MMSE score, and APOEe4 carriership (yes/no). All analyses were performed using the metafor package in R.

Result

Our meta‐analysis showed small but significant associations of diabetes measures with increased (more normal) levels of amyloid‐beta42 (r = 0.08, p = 0.04, Figure 1) and increased (more abnormal) levels of p‐tau (r = 0.09, p = 0.04, Figure 2) and t‐tau (r = 0.10, p = 0.04, graph not shown as comparable to p‐tau). Heterogeneity was high for all outcomes (I2>60%, p<0.05 for Q‐test, wide prediction intervals). Meta‐regression analyses showed that heterogeneity in CSF amyloid could partly be explained by setting, as the association between diabetes measures and amyloid was only present in memory clinic studies as compared to population studies (difference estimate = 0.14, p = 0.03). Similarly, studies with more dementia cases showed a stronger association with amyloid (slope estimate = 0.0029, p = 0.001). No other moderating effects were found.

Conclusion

Our findings suggest that diabetes measures are associated with tau‐related neurodegeneration that is independent from amyloid. This is valuable for improving diagnostics and treatment of patients with diabetes and AD.
Metabolites and Brain Age in a Puerto Rican Cohor
Authors: Gordon Scot , Koo Bang‐Bon , Scott Tammy , Bigornia Sherman J , Bhadelia Rafeeque , Tucker Katherine L , Palacios Natalia
Published: December 2023

Background

Several studies have examined metabolomic profiles in relation to Alzheimer’s disease and related dementia ADRD risk, however, few studies have focused on minorities, such as Latinos or examined MRI‐based outcomes.

Methods

This study examined the association between plasma metabolites and MRI‐derived AD/ADRD markers including brain age deviation and hippocampal volume in the Boston Puerto Rican Health Study (BPRHS). We used multiple linear regression, adjusted for covariates, to examine the association between metabolite concentration at baseline and brain age deviation in the Boston Puerto Rican health Stdy. Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. Brain age deviation was calculated as chronologic age minus MRI‐estimated brain age, representing the rate of biological brain aging relative to chronologic age. We further examined if metabolites associated with brain age were similarly associated with hippocampal volume.

Results

Several metabolites including isobutyrylcarnitine, propionylcarnitine (BCAA metabolism), phenylacetylglutamine, phenylacetylcarnitine (acetylated peptides), p‐cresol‐glucuronide*(tyrosine metabolism), and trimethylamine N‐oxide (TMAO) were inversely associated with brain age deviation. Taurocholate sulfate, a bile salt, was associated with better brain aging.

Conclusions

The metabolites identified in this study are generally consistent with prior literature and highlight a role of branched chain amino acids, TMAO and microbially derived in cognitive decline in cognitive decline.
The cerebrospinal fluid A‐T+ Alzheimer disease biomarker profile: prevalence and clinical relevance
Authors: Eriksson Pontus , Simrén Joel , Brum Wagner Scheeren , Ennis Gilda E. , Kollmorgen Gwendlyn , Carboni Margherita , Langhough Rebecca E , Jonaitis Erin M. , Van Hulle Carol A. , Betthauser Tobey J , Carlsson Cynthia M. , Asthana Sanjay , Ashton Nicholas J. , Johnson Sterling C , Shaw Leslie M. , Blennow Kaj , Andreasson Ulf , Bendlin Barbara B , Zetterberg Henrik
Published: December 2023

Background

The cerebrospinal fluid (CSF) amyloid β‐negative and tau‐positive (A‐T+) biomarker profile, as defined by normal amyloid β42/40 ratio (Aβ42/40) and increased phosphorylated tau (p‐tau), is sometimes seen in daily clinical practice. However, knowledge is lacking on its prevalence and whether patients with this profile are at risk for biological disease progression and cognitive decline.

Method

In this study, data from four cohorts were included: UGOT (the clinical laboratory database at Sahlgrenska University Hospital, Gothenburg), Alzheimer’s Disease Neuroimaging Initiative (ADNI; cognitively unimpaired [CU] and mild cognitive impairment [MCI] individuals), Wisconsin Registry for Alzheimer’s Prevention, and Wisconsin ADRC cohorts (latter two analyzed jointly, “WISC”; predominantly CU individuals). Repeated measures of cognitive decline (modified preclinical Alzheimer’s composite [mPACC] in ADNI, and PACC‐3 in the WISC sample), amyloid accumulation (only in ADNI: [18F]‐florbetapir amyloid positron emission tomography [PET]) neurodegeneration (only in ADNI: magnetic resonance imaging [MRI], [18F]‐fluorodeoxyglucose PET [FDG‐PET]), and cross‐sectional tau PET ([F18]‐flortaucipir in ADNI and [F18]‐MK6240 in WISC) were used as exposures.

Result

In the UGOT cohort, a total of 7679 individuals were included (46

Conclusions

6% women; mean [SD] age, 71.0 [8.3] years). Further, 970 individuals from ADNI (45.8% women, mean [SD] age, 72.8 [7.0]), and n = 519 individuals from WISC (66.7% women, mean [SD] age, 59.7 [7.3]) cohorts were included. The prevalence of the A‐T+ profile in the UGOT cohort was 4.1%, compared with A+T+ that constituted 36%, A‐T‐ 42%, and A+T‐ 17%. In ADNI and UGOT, A‐T+ had higher concentrations of Aβ42 and Aβ40 compared to A‐T‐ individuals. The prognosis of CSF biomarker profiles was determined with linear mixed effects models (ADNI and WISC). The A‐T+ profile, compared with A‐T‐, presented no statistically significant rates of cognitive worsening (ADNI and WISC p>0.05), or in longitudinal changes in Aβ‐PET, FDG‐PET, and hippocampal atrophy (all p>0.05), within the ADNI subsample. Cross‐sectionally, A‐T+ individuals had similar tau‐PET uptake to A‐T‐ individuals (p>0.05).

Conclusion

The CSF A‐T+ profile is to be considered clinically benign, as individuals with this profile do not have a higher rate of cognitive decline compared with biomarker‐negative individuals and do not display signs of amyloid accumulation or progressive neurodegeneration.
Effect of AZP2006, a new treatment for Alzheimer’s Disease and Progressive Supranuclear Palsy, in the Restoration of Lysosomal Homeostasis via the Progranulin‐Prosaposin Axis
Authors: Callizot Noelle , Estrella Cecilia , Henriques Alexandre , Verwaerde Philippe
Published: December 2023

Background

Progranulin (PGRN) is a secreted pleiotropic growth factor primarily expressed in neurons and microglia that regulates neuroinflammation, neurite branching and outgrowth. PGRN has been identified as a Cathepsin D chaperone, suggesting a role in lysosomal proteolysis. PGRN together with Prosaposin (PSAP) have been proved to be physiologically involved in lysosomal lipid catabolism. PSAP physically interacts with PGRN and facilitates glycosphingolipid degradation upon lysosomal processing, serving as activators of various lysosomal lipases. Thus, PGRN and PSAP play an essential role in the regulation of lysosomal homeostasis. Reduced lysosomal protein levels and activity, as well as accumulation of toxic proteins, have been observed in age‐dependent neurodegenerative diseases. The impact of the disturbance of the PGRN‐PSAP axis in these diseases is not yet fully understood.

AZP2006 (INN: Ezeprogind) is a small molecule currently under development for the treatment of Progressive Supranuclear Palsy (PSP, Ph2a completed) and Alzheimer’s Disease (AD). AZP2006 was proved to protect neurons, to increase synaptogenesis and to reduce neuroinflammation in different models of proteinopathies. Importantly, its neuroprotective properties were fully abolished in absence of PGRN or PSAP. Although its exact mode of action (MOA) is still unclear, AZP2006 has been proved to target lysosomes and bind the complex PGRN‐PSAP. Considering this information, the AZP2006 lysosomal MOA was further investigated.

Method

Aged (18mo) C57Bl6 mice receiving Aβ1‐42 oligomers bilaterally injected into the CA1 area of the hippocampus, were orally treated (gavage) with AZP2006 (1 or 2mg/kg/day) for 22 days. At the end of the treatment, the brain, CSF and plasma of the animals were collected. Lysosomal markers were investigated (LAMP‐2, LC‐3b, PGRN, PSAP, α‐Syn and glycosphingolipids contents). Histological analysis of the CA1 hippocampal area was performed (LAMP‐2, LC‐3b and α‐Syn in neurons and microglial cells). In addition, plasma and CSF samples of PSP patients generated from PSP Ph2a were analyzed.

Result

AZP2006 displayed beneficial effects in the Ab1‐42 oligomers injured aged mice. AZP2006 was able to correct the lysosomal dysfunction and to restore the lysosomal homeostasis.

Conclusion

AZP2006 represents an original therapeutic approach to protect the PGRN‐PSAP balance that is fundamental for the neuron health.
Levels of plasma ADAM10 and cognitive performance in older adults with and without Alzheimer’s dementia from a middle‐income country
Authors: Grigoli Marina Mantellatto , Pelegrini Lucas Nogueira de Carvalho , Manzine Patricia Regina , Cominetti Márcia Regina
Published: December 2023

Background

Alzheimer’s Disease (AD) is the most prevalent dementia, and its underdiagnosis rates are still challenging, especially in low and middle‐income countries (LMIC) (Pelegrini et al., 2019). Research suggests the potential benefits of blood‐based biomarkers for accurate diagnosis, and ADAM10 is an example (Oliveira et al., 2020). However, more evidence from LMIC, such as Brazil and other Latin American countries, is necessary (Parra et al., 2022).

Aim

To compare the plasma ADAM10 levels and cognitive performance between healthy older adults and individuals with AD in a Latin American country.

Methods

This is a cross‐sectional study in which healthy older adults (n = 31) and participants with AD (n = 51) had their cognitive performance assessed through MMSE. In addition, a blood sample was collected, and the plasma ADAM10 levels were obtained through SDS‐PAGE and Western‐Blotting analyses. Comparison of means, correlation, and binomial logistic regression analyses were conducted at a significance level of p<0.05.

Results

Most participants were female (61%), whose average age was 76.1 (8.3). The mean years of education and MMSE scores were, respectively, 4.6 (4.1) and 18.8 (8.2). The AD group was older (U = 363.5; p<0.001); had a lower score on MMSE (U = 129; p<0.001), and had higher plasma ADAM10 levels (U = 429; p = 0.001). Correlation analysis revealed a relationship between MMSE score and ADAM10 levels (r = ‐0.225; p = 0.04); age and cognitive performance (r = ‐0.353; p = 0.001); as well as between age and ADAM10 levels (r = 0.324; p = 0.004). Finally, our results suggested that those individuals with higher plasma ADAM10 levels have approximately eleven times more chances of being diagnosed with AD (B = 2.36; S.E. = 0.74; p = 0.001; Exp(B) = 10.63; 95%CI [2.48 – 45.69]).

Conclusion

This study showed that levels of ADAM10 are different between healthy older adults and individuals with AD. Specifically, participants with AD have higher plasma ADAM10 levels. Also, low MMSE scores were correlated with higher ADAM10 plasma levels. Finally, people with higher plasma ADAM10 levels have more chances of being diagnosed with AD.
Using data‐driven approaches to reveal distinct neurocognitive profiles in posterior cortical atrophy
Authors: Chapleau Marianne , Ramanan Siddharth , La Joie Renaud , Miller Zachary , Irish Muireann , Rabinovici Gil D.
Published: December 2023

Background

Posterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing due to neurodegeneration of posterior brain regions (occipito‐parietal and occipito‐temporal areas). Previous findings have reported broader cognitive impairment profiles, but their association with neural correlates remains unclear. In this project we aimed to use principal component analysis to explore the relationship between various cognitive dimensions and FDG‐PET hypometabolism in PCA patients.

Method

We included 59 patients with a clinical diagnosis of PCA (with supporting radiological evidence) from the Memory and Aging Center database at the University of California in San Francisco (Table 1). The sample consisted of 64.4% females, mean age was 63.0 ± 7.6, and mean MMSE was 20.7 ± 5.6 at the diagnostic visit. Participants underwent extensive neuropsychological assessment; these scores were subsequently entered into an orthogonally‐rotated principal component analysis. In a subset of patients with FDG‐PET (N = 24), associations between the emergent cognitive components and whole‐brain hypometabolism were examined to explore neural correlates of cognitive heterogeneity.

Result

Five components explained 72% of overall performance variation in PCA patients: episodic memory, visuospatial function, working memory, verbal generation, and naming/depression (Figure 1). Labels were assigned base on the primary area of greatest cognitive dysfunction. Visualization of component scores suggested systematic performance variation within the PCA sample. The mean metabolism map showed, as expected, predominant hypometabolism in occipito‐parietal and occipito‐temporal regions (Figure 2A). Voxel‐wise correlations revealed that hypometabolism in distinct frontoparietal regions underpinned episodic memory and visuospatial (inferior/superior parietal lobes), working memory and verbal generation (superior/middle frontal gyrus) performance (Figure 2B).

Conclusion

PCA is a cognitively heterogeneous syndrome, where patients can show varying levels of cognitive deficits across episodic and working memory, executive functions, language and affect, over and above canonical visuospatial impairments.
Executive function performance depends on hypertension in individuals with sub‐threshold total Hachinski score
Authors: Flores Jaqueline A , Sudhakar Tejaswi D , Pedersen Taylor J , Anderson Cole E , Peskind Elaine R , Li Ge , Iliff Jeffrey J , Rane Swati ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

Background

The Hachinski Ischemia Scale (HIS) differentiates AD and vascular dementia and is used to include individuals with minimal vascular risk factors in ADNI i.e., HIS ≤ 4. HIS score includes history of hypertension (HMHYPERT), a known risk for mild cognitive impairment (MCI) and vascular dementia. Cerebrovascular disease affects performance on tasks involving executive function, such as, planning and processing speed more than memory. Here, we determined if HMHYPERT scores influences executive functioning in all ADNI3 participants with normal cognition (CN) and MCI even with minimal vascular risks.

Method

We included a total of 272 participants (102 MCI, age = 74± 8 [42F, 50 HMHYPERT>0], MoCA = 23 ±3 and 170 CN, age = 73 ±6, [109F, 62 HMHYPERT>0], MoCA = 26 ±3), who underwent HIS, Trails Making Test B, Clock Drawing and Copy scores for executive function, and The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory Test (LOGMEM) scores for memory performance within 12 months. We converted both memory tests into z‐scores and created a composite memory score. Similarly, we created a composite executive function score. To determine if HMHYPERT was associated particularly with executive function, we ran the linear regression analyses twice for the two composite cognitive scores. The following model was used: Composite score ∼ Normalized Age + Sex + Cognitive status * HMHYPERT.

Result

Executive function: Fig. 1 A shows scores for Trails B, Clock Draw and Clock Copy. The regression analysis showed that executive function was associated with only sex and HYMHYPERT (p<0.05).

Memory function

Fig. 1 B shows scores for Logical Memory and RAVLT tests in CN and MCI. As expected, MCI groups demonstrate the lowest averages compared to CN groups. As expected, regression analysis showed that memory performance was strongly determined by diagnostic status (p<0.001). Age was significantly associated with memory performance (p<0.05). HMHYPERT was only marginally significantly associated with memory performance (p = 0.08).

Conclusion

Using HMHYPERT score as a measure of vascular risk, we observed notable differences in executive function. Although HIS scores ≤ 4 minimize vascular pathology in ADNI3, cognitive performance is still associated with these scores.
Prevention of ferroptosis by the Alzheimer multifactorial therapeutic agent E2F4DN correlates with reduced neuronal tetraploidization
Authors: Lopez‐Sanchez Noelia , Cano‐Daganzo Vanesa , Garrido‐García Alberto , Frade Jose María
Published: December 2023

Background

Somatic mutations accumulate during aging in human neurons (Science 2018;359:555‐559), resembling the progressive increase of somatic tetraploid neurons that is observed in the human entorhinal cortex, which precedes the neuropathological hallmarks of Alzheimer’s disease (AD) (Neurobiol. Aging 2017;56:50‐66). Oxidative stress can trigger lipid peroxidation, which can mediate somatic mutations and ferroptosis in neurons. E2F4 is a transcription factor that regulates the expression of genes involved in the oxidative stress response (Int. J. Mol. Sci. 2022;23:12093). A modified version of E2F4, unable to become phosphorylated in two conserved Thr residues by the stress kinase p38MAPK (E2F4DN), is a multifactorial therapeutic agent against AD. This therapeutic agent prevents pathological neuronal tetraploidization (NT) (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐3039).

Method

To study the connection between somatic mutations and neuronal tetraploidy, we performed whole exome sequencing of diploid and tetraploid neurons isolated from the parietal cortex of AD patients as well as diploid neurons from control individuals. We also studied by qPCR whether oxidative stress‐related genes are modulated by E2F4DN in the cerebral cortex of both WT and 5xFAD mice, a known AD mouse model.

Result

Tetraploid neurons contain a significantly higher proportion of single nucleotide variants (SNVs) as compared to diploid neurons. These SNVs, which showed a molecular signature associated to lipid peroxidation, were exacerbated in DNA repair genes involved in base excision repair. SNVs in cancer‐related genes showed high pathogenicity scores in all cases. In both WT and 5xFAD mice, neuronal expression of E2F4DN reduced the expression of molecular markers of ferroptosis, a process associated with lipid peroxidation. This correlated with reduced NT.

Conclusion

We propose that oxidative stress induces somatic mutations in neurons. When this process stochastically occurs in DNA repair genes, it facilitates the accumulation of SNVs in cancer‐related genes. This would lead to a tumor‐like process triggering NT followed by delayed neuronal degeneration (Am. J. Pathol. 2010;177:15‐20), as previously shown in vitro (Sci. Rep. 2018;8:14316). This mechanism likely participates in the etiology of neurodegenerative diseases including AD. E2F4DN prevents pathological NT likely due to its capacity to regulate oxidative stress response genes even under stressful conditions.
Plasma SNAP‐25 as a potential Alzheimer’s disease biomarker
Authors: Ribaldi Federica , Mendes Augusto J , Zetterberg Henrik , Blennow Kaj , Grötschel Lana , Lathuiliere Aurelien , Garibotto Valentina , Ashton Nicholas J. , Vanmechelen Eugeen , Frisoni Giovanni B
Published: December 2023

Background

Synaptic degeneration and dysfunction are hallmarks of several neurodegenerative diseases, including Alzheimer’s disease (AD). Several studies have shown that the presynaptic protein, synaptosomal‐associated‐protein‐25 (SNAP‐25), is increased in the cerebrospinal fluid (CSF) of AD patients. In the era of ultra‐sensitive immunoassays, the quantification of SNAP‐25 concentration in blood could provide an easily accessible measure of synaptic integrity in AD.

Method

In this pilot study, we investigated 42 participants (n = 23 cognitively unimpaired [CU]; n = 19 MCI or AD dementia patients [CI]) from Geneva University Hospital. A total of 27 participants underwent amyloid positron emission tomography (PET) scans and 14 underwent tau PET scans within 1 year. Global cognition was assessed with Mini Mental State Examination (MMSE). Mann‐Whitney tests were used to assess differences in plasma SNAP25 levels between diagnostic, amyloid (A+/‐) and tau (T+/‐) classification. Furthermore, we used Pearson correlations to assess the association between SNAP25, amyloid centiloid, Tau SUVr and MMSE.

Result

The mean age was 66.9 years +/‐ 7.6 years and 57% were female. SNAP‐25 was significantly increased in CI patients (0.87 pg/mL ±/‐ 0.19) compared to CU participants (0.59 pg/mL ±/‐ 0.11; p>0.001). SNAP‐25 levels were also significantly increased in A+ (0.89 pg/mL ±/‐ 0.18) and T+ (0.92 pg/mL ±/‐ 0.19) individuals compared to A‐ (0.65 pg/mL ±/‐ 0.09; p<0.001) and T‐ (0.717 pg/mL ±/‐ 0.07; p = 0.041). Moreover, we observed a significant correlation between the SNAP‐25 levels and amyloid centiloid (p = 0.016, rho = 0.48), while the correlation was not significant between SNAP‐25 and tau SUVr (p = 0.146, rho = 0.41). Finally, we observed a significant correlation between SNAP‐25 levels and MMSE score (p = 0.033, rho = ‐0.35).

Conclusion

The novel plasma single molecular array (Simoa) can accurately quantify SNAP‐25 in blood plasma. In a pilot study, we observed significantly elevated plasma SNAP‐25 levels in cognitively impaired individuals and amyloid and tau positive individuals. Our findings suggest that SNAP‐25 is a potential biomarker indexing synaptic loss in AD. Further results will extend to a memory clinic cohort of >350 participants to assess its diagnostic and prognostic power and relationship to amyloid, tau, MRI and CSF biomarkers.
Accelerating drug discovery in Alzheimer’s disease through innovative and strategic public‐private partnerships.
Authors: Pullagura Sri Ramulu , Travaglia Alessio
Published: December 2023

Background

The total cost of Alzheimer’s Disease related drug development was estimated to be $5.6 billion, and the timeline was predicted to be approximately 13 years from a pre‐clinical study to the approval by regulatory agencies. No single organization can allocate resources to this extent and successfully conquer the drug development challenges.

Method

To overcome this problem, the Foundation for the National Institute of Health (FNIH) has created cross‐discipline consortia including clinical researchers at NIH, other government agencies, industry, academia and not for profit organizations with a goal to find potential drug targets and biomarkers for Alzheimer’s Disease and reduce the time and cost of Alzheimer’s drug development.

Results

This talk will focus on lesson learned, main achievements, past and ongoing work in large and high‐profile projects including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Accelerating Medicines Partnership® Program for Alzheimer’s Disease (AMP® AD), and leading projects in the Biomarkers Consortium focused on the evaluation of the top‐performing plasma Aβeta, phospho‐Tau and Neurofilament light assays.

Conclusion

These consortia and public‐private partnerships are contributing to discovery and validation of new therapeutic targets and biomarkers for disease progression and treatment response, which will lead to increased clinical trial success and new drugs for patients with Alzheimer’s disease.
Astrocyte Gpc5 overexpression prevents hippocampal synaptic hyperexcitability in APP/PS1 mouse
Authors: Salas Isabel , Paumier Adrien , Switzler Corey , Allen Nicola
Published: December 2023

Background

Astrocytes are essential regulators of synaptic function throughout life. They regulate the formation, maturation and elimination of new synapses, as well as modulate synaptic transmission, and provide nutritional support to neurons. Our lab and others have shown that with healthy aging astrocytes change their properties altering the expression of genes important for synaptic maintenance in brain regions vulnerable to Alzheimer’s disease (AD). We now investigated whether astrocytes present the same age‐associated changes in mouse models of AD. We also assess whether these astrocyte changes are contributing to the synaptic dysfunction and cognitive alterations observed in AD mouse models.

Method

We use BacTRAP technology to isolate hippocampal astrocyte RNA from two different mouse models of Alzheimer’s disease: a model of Tau pathology (MAPTP301S) and amyloidosis (APPswe/PS1dE9). We analyze astrocyte transcriptome at 3 different timepoints: 4, 6 and 12 months, and in male and female mice independently. To assess the contribution of astrocyte alterations to synaptic dysfunction, we manipulate astrocyte gene expression using a viral approach in APP/PS1 mice, and characterized synaptic function using electrophysiology path‐clamp recordings, and spatial learning with Barnes maze test.

Result

Both APP/PS1 and MAPTP301S models showed an upregulation of genes involved in astrocyte reactivity and neuroinflammation and a downregulation of genes important for synaptic support. Among the genes that were downregulated was Glypican 5 (Gpc5), an astrocyte factor important for synaptic maturation and stabilization. Interestingly, Gpc5 downregulation has also been reported in several other human Alzheimer’s disease transcriptional studies. When we overexpress Gpc5 in astrocytes in APP/PS1 mice, we found that APP/PS1 mice injected with the control virus showed an increase postsynaptic frequency in CA1 pyramidal neurons, and this hyperexcitability was no present in APP/PS1 mice overexpressing Gpc5. In addition, preliminary cognitive results from the Barnes maze test suggest that astrocyte Gpc5 overexpression also improves spatial learning in APP/PS1 and WT mice.

Conclusion

This data show that astrocyte Gpc5 downregulation might contribute to synaptic dysfunction in AD. Overexpressing Gpc5 in astrocytes prevents synaptic hyperexcitability in APP/PS1 mice. These results open exciting new venues for using astrocytic factors as novel targets in AD.
Phospholipase D3 drives microglial response to amyloid pathology in Alzheimer’s disease
Authors: Rosene Matthew J , Danhash Emma , You Shih‐Feng , Iyer Abhirami Kannan , Hsu Simon , de Sa Lopes Mariana Acquarone , Brase Logan , Verbeck Anthony , Martinez Rita , Wallace Clare E , Li Zeran , Yan Ping , Drager Nina , Sattler Sydney M , Mahan Thomas E , Macauley Shannon L , Holtzman David M. , Benitez Bruno A. , Kampmann Martin , Cruchaga Carlos , Harari Oscar , Cirrito John R , Lee Jin‐Moo , Goate Alison , Karch Celeste M.
Published: December 2023

Background

Amyloid‐beta (Aβ) plaque formation is a well‐established hallmark for Alzheimer’s disease (AD). However, the processes behind plaque formation are not understood. Previous work from our group identified rare coding variants for PLD3, with one variant in particular, p.A442A, disrupting a splicing enhancer binding site within the mRNA transcript. In this study, we present findings that PLD3 regulates Aβ clearance in the brain through both cell autonomous and non‐autonomous means.

Method

To replicate the splicing effect observed in patient brain samples in vitro, PLD3 p.A442A expressing induced pluripotent stem cells (iPSCs) were differentiated into neurons or microglia and evaluated for extracellular Aβ and Aβ uptake, respectively. In an APP/PSEN1xPld3KO mouse model, Aβ dynamics were assessed with in vivo microdialysis and plaque pathology was assessed with immunohistochemistry. Frozen cortical tissue from these mice was analyzed through bulk RNAseq to identify transcriptomic and molecular changes that are attributed to Pld3 deficiency. PLD3 expression was assessed in an independent single‐cell RNAseq (scRNAseq) dataset from iPSC‐derived microglia to assess a potential cell‐autonomous role for PLD3 in microglia.

Result

Transcriptomics from human samples reveal a significant decrease of PLD3 expression in AD brains versus controls, particularly in the brain regions most susceptible to amyloid pathology. Similar to PLD3‐variant brains, iPSC‐derived neurons carrying PLD3 p.A442A exhibited alternative splicing and displayed elevated Aβ levels in the conditioned media. Loss of Pld3 in APP/PSEN1 mice led to increased interstitial levels of Aβ and reduced Aβ clearance. Immunohistochemistry revealed an increase in diffuse, nonfibrillar plaque area and reduced microglial recruitment in APP/PSEN1xPld3KO. Transcriptomics data from brain tissue in these mice revealed altered expression of genes that define the disease associated microglia signatures. To begin to understand the role of PLD3 in microglia, we analyzed scRNAseq from CRISPRi screen in iPSC‐derived microglia. We found that PLD3 expression is enriched in interferon‐associated microglia. Finally, we demonstrate that iPSC‐derived microglia carrying PLD3 p.A442A exhibit reduced internalization of Aβ and myelin, suggesting a defect in phagocytic capacity.

Conclusion

Together, we show that PLD3 plays a critical role in the brain by facilitating the microglial response to Aβ plaque pathology, modulating plaque composition.
APNmAb005, an anti‐tau antibody targeting synaptic tau oligomers, in Phase 1 for treatment of Alzheimer’s Disease and primary tauopathies
Authors: Tai Chin‐Yin , Ma Haou‐Tzong , Li Chung‐Lin , Fang Wu Meng‐ , Wang Silas , Wu Chia‐Lin , Lai Yen‐Ting , Serrano Geidy E , Beach Thomas G , Margolin Richard A , Zhang Lili , Jang Ming‐Kuei , Navia Bradford
Published: December 2023

Background

Accumulation of tau oligomers at the synapses in Alzheimer’s disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers.

Method

APNmAb005 was selected as a clinical candidate from APRINOIA’s antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway.

Result

Epitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects.

Conclusion

APNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability.
Modulation of microglial function by neuronal expression of the Alzheimer multifactorial therapeutic agent E2F4DN is mediated by a soluble factor
Authors: Ramón‐Landreau Morgan , Lopez‐Sanchez Noelia , Frade Jose María
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder in which altered immune response is an important etiological factor (Cell Rep. 2019;27:1293.e6‐1306.e6, Nature 2019;575:669‐673). The transcription factor E2F4 regulates gene networks affected in AD (Interdiscip. Sci. 2019;11:226‐236), thus constituting a potential target for intervention. Neuronal expression of a dominant negative form of E2F4 (E2F4DN), which cannot be phosphorylated in two conserved Thr residues, can attenuate microgliosis in a mouse model of AD (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐30392), as evidenced by the reduction of area occupied by microglia (i.e. Iba1‐positive cells). Communication between neurons and microglia is essential to regulate microglial activation and neuroprotection. The loss of this communication can cause microglia overactivation and produce persistent inflammation, finally resulting in the exacerbation of the neuropathology (Neural Regen. Res. 2019;14:1499‐1502).

Method

Mouse cortical neurons were cultured and maintained for 9 days in vitro (DIV) for maturation. Neurons were then transfected with an E2F4DN adenoviral (Ad5) vector, or a control EGFP Ad5 vector. After 48 h, rat microglia were treated for 24 hours with the conditioned media, and then fixed and immunostained with the microglia marker Iba1. The size of these cells was analyzed as a readout of the glial inflammatory activity (Sci. Rep. 2017;7:1576).

Result

Microglial cell size was analyzed from images obtained in the fluorescence microscope. This would determine if any soluble factor secreted by neurons that express E2F4DN, but not by neurons that express EGFP, is capable of inducing morphological changes that may reflect functional changes in this cell type. A reduction in the size of microglia was observed when the conditioned medium came from neurons expressing E2F4DN. These results show the existence of a differential communication mechanism between neurons and microglia depending on the expression of E2F4DN.

Conclusion

We suggest that there is an E2F4DN‐dependent neuron‐microglia communication based on soluble factors such as those described by Simon et al. (Neuroscience 2019;405:24‐34). Altogether, our data are consistent with a beneficial immune response elicited by neurons expressing E2F4DN, a molecule proposed as a multifactorial therapeutic agent against AD.
Understanding the electrochemical interaction between the hybrid bilayer lipid membranes and amyloid‐β
Authors: Hassan Qusai , Kerman Kagan
Published: December 2023

Background

Biomimetic membrane systems can be deposited onto conductive metal surfaces to study the physical properties of membranes as well as the behaviour of proteins within these membranes using electrochemical and surface analytical techniques [1]. Although there are several types of biomimetic membrane, hybrid bilayer lipid membranes (HBLMs) have attracted wide interest. Traditionally, HBLMs have been developed by electrodepositing alkanethiol self‐assembled monolayers onto gold surfaces, which can then be further modified by depositing a secondary phospholipid layer to form the HBLM. Although HBLMs have been widely regarded due to them being robust, relatively straightforward to make, as well as being easy to modify according to the users needs, several concerns surround HBLMs including their reduced fluidity compared to true cell membranes. This is due to the alkanethiol layer being crystalline in nature and more densely packed, resulting in difficulty to reconstitute transmembrane proteins within them.

Method

Screen‐printed carbon electrodes are modified with diazonium based phenyl alkyl groups using different protocols to evaluate the biomimetic differences of these novel HBLMs. 2,2‐diphenyl‐1‐picrylhydrazyl is used to prevent the formation of polyaryl layers on the surface of the electrode, hence limiting the electrodeposition to a monolayer. The HBLMs are formed by depositing the second layer in the form of dihexadecyl phosphate, which are analyzed using differential pulse voltammetry, ellipsometry, and X‐ray photoelectron spectroscopy.

Result

The different HBLMs presented are embedded with amyloid‐β1‐42 (Aβ42), the hallmark protein implicated in Alzheimer’s Disease, to assess the protein‐membrane interactions using HBLMs. Aβ42 is known to aggregate to form dimers, oligomers, fibrils, and plaques. Hence using electrochemical techniques, we are able to monitor the aggregation of Aβ42 in the HBLMs. The aggregation process was accelerated by the presence of the bilayer membrane.

Conclusion

The electrochemical platform presented here enables us to understand how the interaction of amyloid‐β with the bilayer membrane can alter the aggregation pathways and also affect the formation of toxic oligomer species.

References: [1] Fini, H., Hassan, Q., Noroozifar, M. & Kerman, K. Electrografting a Hybrid Bilayer Membrane via Diazonium Chemistry for Electrochemical Impedance Spectroscopy of Amyloid‐β Aggregation. Micromachines 13, 574 (2022).