bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundProgranulin (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.MethodAged (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.ResultAZP2006 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.ConclusionAZP2006 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

AbstractBackgroundAlzheimer’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).AimTo compare the plasma ADAM10 levels and cognitive performance between healthy older adults and individuals with AD in a Latin American country.MethodsThis 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.ResultsMost 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]).ConclusionThis 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

AbstractBackgroundPosterior 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.MethodWe 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.ResultFive 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).ConclusionPCA 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

AbstractBackgroundThe 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.MethodWe 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).ConclusionUsing 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

AbstractBackgroundSomatic 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).MethodTo 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.ResultTetraploid 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.ConclusionWe 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

AbstractBackgroundSynaptic 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.MethodIn 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.ResultThe 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).ConclusionThe 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

AbstractBackgroundThe 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.MethodTo 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.ResultsThis 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.ConclusionThese 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

AbstractBackgroundAstrocytes 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.MethodWe 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.ResultBoth 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.ConclusionThis 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

AbstractBackgroundAmyloid‐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.MethodTo 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.ResultTranscriptomics 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.ConclusionTogether, we show that PLD3 plays a critical role in the brain by facilitating the microglial response to Aβ plaque pathology, modulating plaque composition.