# Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation

Thi Hong Van Nguyen, Francois Ferron, Kazuma Murakami

► To cite this version:

Thi Hong Van Nguyen, Francois Ferron, Kazuma Murakami. Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation. ACS Chemical Biology, 2025, 20 (5), pp.983-992. 10.1021/acschembio.5c00153. http://onlinelibrary.wiley.com/doi/abs/10.1021/acschembio.5c00153

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1 **Perspective**

2

3 Neurotoxic implications of human coronaviruses in neurodegenerative diseases:

4 A perspective from amyloid aggregation

5

6 Thi-Hong-Van Nguyenª, Francois-patrice Ferronᵇ,ᶜ, and Kazuma Murakamiª,⁺

7

8 ªDivision of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto

9 University, Kyoto, Japan

10 ᵇAix Marseille Univ, CNRS-Architecture et Fonction des Macromolécules Biologiques

11 (AFMB) UMR7257, Marseille, France

12 ᶜEuropean Virus Bioinformatics Center, Jena, Germany

13

14 *Corresponding author

15 murakami.kazuma.4v@kyoto-u.ac.jp

16

17 Authors' Information

18 ORCID 0000-0003-2133-9161 (T.-H.-V.N.)

19 ORCID 0000-0002-8351-4992 (F.R.)

20 ORCID 0000-0003-3152-1784 (K.M.)

21

22
Summary

Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-
OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three,
classified as Betacoronaviruses, are highly transmissible and have caused severe
pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms
such as dry cough, fever, and breath shortness, which can progress to acute respiratory
distress syndrome and death. Beyond respiratory effects, increasing evidence links
HCoVs to neurological dysfunction. However, distinguishing direct neural complications
from preexisting disorders, particularly in the elderly, remains challenging. This review
examines the association between HCoVs and neurodegenerative diseases like
Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral
sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological
effects of HCoV infections and their differential impact across age groups and sexes. A
key aspect of this review is the investigation of the sequence and structural similarities
between amyloidogenic and HCoV proteins, which can provide insights into potential
neuropathomechanisms.
## INTRODUCTION

The *Coronaviridae* family, classified under the order *Nidovirales*, comprises three subfamilies, which are as follows: *Orthocoronavirinae*, *Letovirinae*, and *Pitovirinae*. The *Orthocoronavirinae* subfamily is further divided into four genera based on phylogenetic clustering: *Alphacoronavirus*, *Betacoronavirus*, *Gammacoronavirus*, and *Deltacoronavirus*.¹ Human coronaviruses (HCoVs), which infect both humans and animals, belong to the *Alphacoronavirus* and *Betacoronavirus* genera.² Among them, HCoV-229E and HCoV-NL63 are classified as *Alphacoronaviruses*. Meanwhile, HCoV-OC43, HCoV-HKU1, MERS-CoV, severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and SARS-CoV-2 belong to the *Betacoronavirus* genera. HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 are widely distributed, and they collectively account for 10%–30% of upper respiratory tract infections in adults. Due to global travel and migration, MERS-CoV and SARS-CoV-1 have spread across multiple continents including Africa, the Americas, Europe, and Australia, thereby posing significant public health threats.³ More recently, coronavirus disease 2019 (COVID-19) attributed to SARS-CoV-2 led to a global pandemic, causing horrific devastation in the public health system, global economy, and social structures (https://iris.who.int/handle/10665/345300).

HCoV-OC43 consists of four genotypes (A–D), with genotype D emerging via recombination events. Molecular analyses of the spike and nucleocapsid genes indicate shifting of the genotype prevalence: genotype A in the 1950s, genotypes B and C in the 1980s, genotype B in the 1990s, and genotype C from the late 1990s to the early 2000s. Genotype D was first identified in 2004.⁴ HCoV-229E, initially recognized as a common cold virus in the 1960s,⁵,⁶ is now believed to be associated with a spectrum of respiratory illnesses, ranging from self-limiting colds to severe conditions such as bronchiolitis, fever, and pneumonia.⁷ In 2002–2003, an outbreak caused by SARS-CoV-1-related infections started in China.⁸,⁹ SARS-CoV-1 infections caused symptoms such as nasal discharge, fever, malaise, myalgia, headache, dry cough, dyspnea, diarrhea, and chills (rigors). In severe cases, the symptoms rapidly progress to acute respiratory distress syndrome and death.¹⁰ Subsequently, two additional HCoVs, HCoV-NL63¹¹ and HCoV-HKU1,¹² were identified. Both viruses are associated with severe respiratory diseases including bronchiolitis and pneumonia.¹³ In particular, HCoV-NL63 infections are common in children, who often present with cough, fever, and inspiratory stridor. In pediatric cases, they are associated with croup, febrile seizures, and acute gastroenteritis.¹¹,¹³

In 2012, MERS-CoV emerged in Saudi Arabia, causing an outbreak across the Middle East. In the late 2019, SARS-CoV-2 was identified as a causative agent of COVID-19, which resulted in hundreds of millions of infections worldwide. The actual fatality rate (2019–2021) remains unclear. However, due to its severe global impact, the World Health Organization declared the COVID-19 pandemic in 2020. The clinical characteristics of SARS-CoV-2 infections are similar to those of MERS-CoV and SARS-CoV-1 infections. However, SARS-CoV-2 infection is associated with more severe complications such as lymphopenia, severe pneumonia, and acute renal failure. Elderly
patients are at higher risks of severe outcomes. Meanwhile, children generally experience mild or asymptomatic infections (https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-covid-19).

Over the last two decades, three major coronavirus outbreaks—SARS-CoV-1 (2002–2003), MERS-CoV (2012, 2015), and SARS-CoV-2 (2019–2021)—have emphasized the increasing threat caused by coronaviruses to global health. Their genetic diversity and high recombination potential enable interspecies transmission, thereby raising concerns about the emergence of novel HCoVs. Their impact on the respiratory, gastrointestinal, and renal systems is well-documented. Nevertheless, their neurochemical consequences remain underexplored. Emerging evidence has shown that HCoVs can directly or indirectly affect the central nervous system (CNS). Further, CNS damage induced by SARS-CoV-2 may accelerate neurodegenerative diseases (dementia), increasing their incidence and progression rates.¹⁴⁻¹⁶

In particular, the neurochemical effects of HCoV infections have been a cause of concern. Several studies have revealed that SARS-CoV-2 can induce neuroinflammation, alter neurotransmitter levels, and disrupt protein homeostasis. Notably, the structural similarities between amyloid proteins and specific HCoV proteins may play a role in protein misfolding and aggregation, the mechanisms implicated in Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), and mixed disorders (dementia).¹⁷ Considering these challenges, prioritizing research on the neurochemical effects of HCoVs is essential, particularly for vulnerable populations such as the elderly and children. This review aimed to comprehensively analyze (1) the neurological impact of HCoVs across different age groups and sexes, (2) the differences between the neurological complications and neurodegenerative diseases caused by HCoVs, and (3) the potential neurochemical associations between the seven known HCoVs and various neurodegenerative diseases.

# 1. Neurological Complications Related to HCoVs

In patients with HCoV-induced acute respiratory diseases, hypoxia can often lead to brain edema, potentially resulting in neurological manifestations. Nevertheless, HCoVs can also affect the CNS via other mechanisms. These viruses invade neural cells, leading to various neurological symptoms and conditions. The neurological complications associated with HCoVs are outlined below (Table 1).

## 1.1 Less Virulent HCoVs

The neurologic complications caused by less virulent human coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) remain underexplored. This is because these viruses are not typically related to widespread infections or severe public health threats. As a result, research on their neuronal effects is limited. However, some
data have revealed that these viruses can contribute to neurological disorders. HCoV-229E and HCoV-OC43 have been implicated in neuroinvasion and neurological conditions such as multiple sclerosis (MS), meningoencephalitis, and acute flaccid paralysis. Notably, HCoV-OC43 has neuroinvasive and neurovirulent properties in animal models. Mice with HCoV-OC43 infections exhibit CNS damage primarily due to virus-mediated neuronal injury rather than immune responses or microglial activation. Acute encephalitis caused by HCoV-OC43 infection is also associated with long-term neuropathological effects in mice.¹⁸ In addition, HCoV-229E has been detected in patients with neurological symptoms, and experimental studies have confirmed its capability to infect human oligodendrocytic and neuroglial cell lines.¹⁹ Moreover, the virus has also been found in the cerebrospinal fluid (CSF) of a child with presumed acute disseminated encephalomyelitis, a rare immune-mediated demyelinating disorder.²⁰

Moreover, previous studies have reported that HCoV-OC43 and HCoV-NL63 infections occur more frequently in children with underlying conditions, potentially leading to severe CNS-related symptoms. For example, HCoV-OC43 is associated with fatal encephalomyelitis in infants aged <2 years. Meanwhile, HCoV-NL63 can be a potential cause of acute encephalitis in humans.²¹ Based on these findings, the neurotropic properties of HCoV-OC43 may extend to other *Betacoronavirus* species. Hence, this finding should be further investigated.¹⁸

## 1.2 Highly Virulent HCoVs

### 1.2.1 SARS-CoV-1

Research on SARS-CoV-1 has provided insights into its neurological sequelae. The virus can cause mild symptoms including anosmia and headache. Meanwhile, in severe cases, patients can present with nausea, seizures, confusion, loss of consciousness, stroke, and polyneuropathy.²² In addition, SARS-CoV-1 is associated with peripheral nervous system (PNS) involvement, leading to neuromuscular symptoms.²² Notably, SARS-CoV-1 can invade the CNS via the olfactory pathway in mouse models.²³ In transgenic mice expressing human angiotensin-converting enzyme 2 (ACE2), SARS-CoV-1 preferentially infects nerve cells rather than lung cells. Even the intranasal administration of the virus at low doses has resulted in fatal outcomes caused by neurologic dysfunction in the medulla oblongata, despite minimal lung infection.²³ Postmortem studies of patients with SARS-CoV-1 infection have revealed signs of neurotropism such as neuronal edema and degeneration.²⁴ Although reports on the detection of SARS-CoV-1 in the CSF are limited, its potential association with encephalitis should be further investigated.

### 1.2.2 MERS-CoV

MERS-CoV, another *Betacoronavirus*, also exhibits neuroinvasive properties with an oligomerization state.²⁵,²⁶ Neurological symptoms typically emerge 2–3 weeks after infection, and they are more common in men and older adults.²⁷ Research on the
neurological manifestations of MERS-CoV remains limited. However, characteristics including Bickerstaff's encephalitis overlapping with Guillain-Barré syndrome, acute disseminated encephalomyelitis, stroke, and other neuropathies have been documented.²⁷ Arabi et al. has revealed that three patients with a confirmed MERS-CoV infection presented with acute neurological symptoms including loss of consciousness and ataxia.²⁸ Brain magnetic resonance imaging scans revealed extensive brain damage, with one patient developing encephalitis and another exhibiting signs of acute disseminated encephalomyelitis.²⁸ The other complications included large-artery cerebral infarctions, intracerebral hemorrhage, and critical illness polyneuropathy.²⁹

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### 1.2.3 SARS-CoV-2

SARS-CoV-2 shares a 79.6% and 50% genomic similarity with SARS-CoV-1 and MERS-CoV, respectively.³⁰ Although both SARS-CoV-1 and SARS-CoV-2 utilize ACE2 as a receptor, MERS-CoV uses dipeptidyl peptidase-4.³¹ Despite these similarities, SARS-CoV-2 exhibits a greater immune evasion, higher transmissibility, and more severe systemic effects, leading to a significantly greater impact on global health. Numerous studies have shown the neurological manifestations of SARS-CoV-2 in adults. These include headache, nausea, dizziness, fatigue, impaired consciousness, myalgia, dysgeusia, anosmia, seizures, and stroke.³² Stroke is more frequently reported with SARS-CoV-2 than with SARS-CoV-1 or MERS-CoV, which is likely because of its stronger proinflammatory and hypercoagulable effects.³³

Older adults with preexisting neurological conditions are at high risk of mortality after SARS-CoV-2 infection.³⁴ Differences in neurological outcomes according to sex have also been observed. In particular, compared with men, women are more likely to experience milder acute-phase symptoms and more long-term complications such as brain fog, fatigue, and depression, possibly due to stronger immune responses.³⁵ Severe neurological symptoms are rare in children. However, approximately 25% of patients exhibit long-term effects such as mood disturbances, sleep disorders, and anosmia.³⁶ The neuroinvasive and neurotropic properties of SARS-CoV-2 may exacerbate CNS inflammation, leading to conditions such as encephalopathy and meningitis. The additional potential routes of CNS entry, such as AD and PD entry, include hematogenous dissemination via compromised skin, optic nerve, and ocular surfaces.³⁷

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## 2. Association between neurodegenerative diseases and HCoVs

It is not a coincidence that human coronaviruses are associated with neurodegenerative disorders. Decades of research has established that HCoVs are both neuroinvasive and neurotropic.³³ Previous studies have shown that neurons, particularly in mice, are the primary targets of HCoV infections, leading to cellular degeneration and death.¹⁸ These characteristics have drawn significant attention to the association between HCoVs and neurodegenerative diseases (dementia), particularly after the COVID-19 pandemic, which has shed further light on this topic.

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200 neurodegenerative disorders. Decades of research has established that HCoVs are both

201 in mice, are the primary targets of HCoV infections, leading to cellular degeneration and

202 death.¹⁸ These characteristics have drawn significant attention to the association

203 between HCoVs and neurodegenerative diseases (dementia), particularly after the

204 COVID-19 pandemic, which has shed further light on this topic.
## 2.1 Neurodegenerative Diseases and Less Virulent HCoVs

In 2000, Arbor et al. identified the presence of the HCoV-229E strain in the brains of patients with AD, PD, depression, schizophrenia, meningoencephalitis, and MS.¹⁸ In addition, the HCoV-OC43 strain was detected in patients with meningoencephalitis and PD. Based on this finding, both HCoV-OC43 and HCoV-229E may contribute to the development of neurodegenerative diseases.¹⁸ In 2004, Yeh et al. detected HCoV-OC43 in the CNS of a child with acute disseminated encephalomyelitis.²⁰ Mouse model experiments revealed that this HCoV strain could induce chronic demyelination. This finding supports the hypothesis that HCoVs may play a role in the pathogenesis of demyelinating diseases.²⁰ In addition, this evidence links myelin destruction with AD. This is because oligodendrocytes are particularly vulnerable to the AD pathology, leading to myelin breakdown and loss of the myelin sheath.³⁸ This further indicates a connection between HCoV-OC43 and AD.

In 2006, researchers have found that the intracerebral inoculation of HCoV-OC43 caused acute encephalitis in mice.³⁹ Surprisingly, the viral mRNA persisted in the brains of the mice that survived for several months. These mice presented with abnormal limb-clasping reflexes and reduced movement several months after infection.³⁹ Based on these results, the genetic material of HCoV-OC43 may persist in the long term in brain cells, potentially contributing to neuronal degeneration. Moreover, the importance of HCoV-OC43 is highlighted by its classification within the *Betacoronavirus* group, along with high-virulence HCoVs. A previous study has shown the serological cross-reactivity between HCoV-OC43 and SARS-CoV-1/2, with preexisting anti-HCoV-OC43 immunity influencing the durability of humoral responses to SARS-CoV-2 vaccination.⁴⁰

## 2.2 Neurodegenerative Diseases and Highly Virulent HCoVs

### 2.2.1 SARS-CoV-1 and MERS-CoV

SARS-CoV-1 can directly affect both the CNS and PNS in humans.²⁴ There is limited evidence on neurodegeneration associated with SARS-CoV-1. However, pathological examinations have revealed neuronal necrosis, gliocyte hyperplasia, edema, and focal neuronal degeneration.⁴¹,⁴² Patients with infection present with neuro-musculoskeletal symptoms. Therefore, SARS-CoV-1 may exacerbate neurodegenerative conditions such as MS.²² However, due to the finite duration of the SARS-CoV-1 outbreak, no clinical studies have definitively linked this virus to long-term neurodegenerative diseases such as AD, PD, and ALS. Similarly, MERS-CoV can enter the CNS and cause widespread brain impairments. There are no definitive clinical studies connecting MERS-CoV to neurodegenerative diseases. However, symptoms such as loss of consciousness, confusion, fatigue,²⁸,⁴³ and ataxia²⁸ in patients with MERS resemble those associated with AD, ALS, and MS.

### 2.2.2 SARS-CoV-2
The mortality of SARS-CoV-2 infections (approximately 2.3%) is lower than that of SARS-CoV-1 (9.5%) and MERS-CoV (34%) infections.⁴⁴ However, due to its widespread impact, studies investigating its long-term neurological effects should be performed. Emerging evidence suggests a close association between SARS-CoV-2 and neurodegenerative diseases. Verkhratsky et al. have reported that SARS-CoV-2 influences the CNS via several mechanisms including acute systemic inflammation, brain ischemia caused by respiratory failure, and increased thrombosis and stroke.⁴⁵ Enhanced thrombosis can exacerbate symptoms in patients with AD. In addition, SARS-CoV-2-induced neuronal damage may accelerate the onset or progression of neurodegenerative diseases caused by neuroinflammation, oxidative stress, and cytokine storms.⁴⁶,⁴⁷ These processes promote neuronal death and protein aggregation hallmarks of diseases such as AD, PD, and ALS.⁴⁸,⁴⁹ For example, protein aggregation includes amyloid beta (Aβ) and tau neurofibrillary tangles in AD as well as misfolded alpha synuclein (αSyn) in PD, Lewy body dementia, and multiple system atrophy. Meanwhile, aggregated TAR DNA-binding protein 43 (TDP-43) is involved in ALS, frontotemporal lobar degeneration, AD, and PD.¹⁷,⁴⁸,⁵⁰⁻⁵² Moreover, Aβ and αSyn deposition may be observed in the CSF in early PD.⁵³

Research has revealed that elderly patients with preexisting dementia or AD are more susceptible to severe SARS-CoV-2 symptoms and that they exhibit higher mortality rates.⁵⁴ Further, SARS-CoV-2 may increase the risk of lifetime PD⁵⁵ and CJD.⁵⁶ Patients with ALS and MS who developed SARS-CoV-2 infection may also experience intensified symptoms. Meanwhile, patients with prion disease can exhibit accelerated disease progression.²²,⁵⁷ Recent research has emphasized cases where SARS-CoV-2-induced neuroinflammation and protein misfolding processes may contribute to the rapid progression of prion diseases.⁵⁸ Moreover, Lukiw et al.⁵⁹ showed that SARS-CoV-2 infection can exacerbate prion-related protein aggregation, leading to worsened clinical outcomes in affected individuals.

## 2.3 Mechanism of SARS-CoV-2-Associated Neurodegenerative Diseases

The pathogenic mechanisms of SARS-CoV-1, including cytokine dysregulation, aberrant immune responses, immune cell damage, direct target cell infection, ACE2 downregulation, and genetic factors, may also apply to SARS-CoV-2 because of their high genetic similarity.⁶⁰ Evidence confirms that neurons, cerebrospinal fluid, and gliocyte are the primary targets of SARS-CoV-2. However, the exact mechanisms by which HCoVs affect the CNS and PNS remain poorly understood.

### 2.3.1 Coaggregation-Mediated Mechanism

Due to the key role of protein aggregation, essential amyloidosis, including Aβ, αSyn, tau, TDP-43, and HuPrP, have been a topic of interest. To continue with the abovementioned research, the sequence and structure comparisons between some peptides of the SARS-CoV-2 S-protein and Aβ, αSyn, tau, TDP-43, and HuPrP were
performed (Figure 1). These findings underscore the need to further investigate the
molecular interplay between viral proteins and amyloidogenesis, as such interactions
may provide critical insights into the long-term neurological consequences of SARS-
CoV-2 infection. Understanding these mechanisms could open avenues for targeted
therapeutic interventions aiming to mitigate virus-induced neurotoxicity and its
contribution to neurodegenerative diseases.

SARS-CoV-2 spike proteins (S-protein) contain sequences resembling prion-like
proteins, potentially triggering neurodegeneration.⁶¹ Growing evidence has suggested
that this S-protein may interact with amyloidogenic proteins, potentially contributing to
neurodegenerative processes (Table 2). Moreover, the S-protein can induce amyloid-
like fibril formation, facilitating protein misfolding and aggregation.⁶¹ This interaction may
exacerbate amyloid Aβ and tau pathology in AD⁶² or promote αSyn aggregation in
PD,⁶³,⁶⁴ thereby accelerating disease progression. In human cells, SARS-CoV-2 S-
proteins form amyloid fibrils based on the cleavage of the neutrophil elastase. A
mechanism for the amyloid fibril formation of the S-protein has been proposed.
Specifically, the cross-seeding of Spike532 in seeding HuPrP and Spike601 in seeding
Aβ can be associated with the increased risk of CJD and AD after COVID infections. In
addition, the signal sequence peptide and fusion peptides 1 and 2 (NSP6, ORF10, and
NSP11) from both SARS-CoV S-proteins can form amyloid aggregates.⁶⁵,⁶⁶ In particular,
the sedimentation of SARS-CoV-2 NSP11 is toxic to mammalian cells.⁶⁶ In addition,
SARS-CoV-2 S-protein enhances the stability of amyloid fibrils, potentially increasing
their neurotoxicity and persistence in neural tissues.⁶⁷ The SARS-CoV-2 S-protein
induced the interaction of TDP-43 and HuPrP as well as Aβ, αSyn, and tau, which are
potentially linked to the neuropathomechanism of the associated neurodegeneration.⁶⁸
Specifically, the heparin-binding site on the S1 in the viral surface might assist amyloid
binding to facilitate the pathology. The resulting protein aggregates may trigger microglial
activation, oxidative stress, and chronic neuroinflammation, all of which are hallmarks of
dementia. Further, recent findings have revealed that S-protein interactions with
amyloidogenic peptides may contribute to blood-brain barrier dysfunction, thereby
allowing the infiltration of proinflammatory mediators and worsening
neurodegeneration.⁶⁹

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2.3.2 Immune-Mediated Mechanism

Seven genes (HSP90AA1, ALDH2, CAV1, COMT, MTOR, IGF2R, and HSPA1A) have been implicated in both viral infections and neurodegenerative processes via their involvement in molecular pathways such as mitogen-activated protein kinase and nuclear factor kappa B signaling.⁷⁰ These pathways regulate key cellular processes, including stress responses, inflammation, and apoptosis, which are essential in the progression of diseases such as AD and PD. Recent studies have found that these genes may mediate the molecular association between SARS-CoV-2, SARS-CoV-1, and MERS-CoV and neurodegeneration, thereby highlighting their potential role in

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328 intensifying neuronal damage and disease pathology.⁷⁰ Microglial activation, 329 mitochondrial reactive oxygen species production, and neuroinflammation are also 330 associated with the effect of long COVID-19 on neurodegeneration.⁷¹ In addition, AREG+ 331 dendritic cells were found in the CSF of patients with MS. However, their presence in 332 individuals with COVID-19 infection must be further investigated. These cells, which are 333 known for their role in promoting tissue repair and modulating immune responses, have 334 been observed in higher numbers in neuroinflammatory conditions. Their potential 335 involvement in SARS-CoV-2-associated neuroinflammation indicates that they can play 336 an essential role in mediating immune responses within the CNS.⁷² The antibodies 337 myelin oligodendrocyte glycoprotein and optic neuritis cause myelitis inflammation and 338 progressive demyelination in patients with COVID. Importantly, myelin sheath injury 339 affects neuronal signals or neuronal damage leading to AD and vascular dementia. 340 Therefore, the quantity of antibodies myelin oligodendrocyte glycoprotein and the cause 341 of demyelination may be an important biomarker of cognitive impairment and dementia 342 in patients with COVID. Understanding their function in COVID-19 could provide insights 343 into long-term neurological complications and the progression of diseases such as MS 344 and other neurodegenerative disorders. 345

346

### 2.3.3 Receptor-Mediated Mechanism

347 ACE2 is a primary receptor for SARS-CoV-1,⁷³ HCoV-NL63,⁷⁴ and SARS-CoV-2.⁷⁵ 348 SARS-CoV-2 has a significantly high affinity for ACE2 receptors in the CNS. In addition, 349 SARS-CoV-2 S-protein interacts with proteases such as TMPRSS2 and Cathepsin L and 350 co-factors such as neuropilin 1, thereby enabling cellular invasion. Neuropilin 1 plays a 351 critical role in neuronal development, and it may facilitate neuroinvasion.⁷⁶,⁷⁷ The 352 association between S-proteins and ACE2 receptors downregulates the expression of 353 ACE2, thereby increasing angiotensin II levels and worsening neurological 354 complications.⁷⁸ 355

356

### Conclusions and future perspective

357 Infections caused by HCoVs, particularly HCoV-OC43 and HCoV-NL63, are 358 frequently acquired in childhood, often in children with underlying conditions.¹¹,¹³ 359 Although these infections are typically mild, accumulating evidence suggests that they 360 may pose a significant risk of CNS-related complications. Further, HCoV-OC43 and 361 HCoV-229E are associated with the pathogenesis of neurodegenerative diseases, 362 including AD, PD, and depression.¹⁸ Animal models provide insights into the neurotropic 363 nature of coronaviruses. In transgenic mice expressing human ACE2, neurons, rather 364 than lung cells, can be the primary targets of SARS-CoV infections.²³ In contrast, MERS- 365 CoV disproportionately affects men and older individuals, with more pronounced 366 neurological manifestations compared with women. Interestingly, women exhibit milder 367 acute symptoms and lower fatality rates in early-stage SARS-CoV-2 infections. However, 368 they are more likely to experience long-term neurological sequelae. 369

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A remarkably concerning finding is that elderly patients with preexisting neurological conditions often exhibit acute exacerbations after infections with SARS-CoV-1, MERS-CoV, or SARS-CoV-2. In particular, COVID-19 accelerates the progression of neurodegenerative diseases such as AD, PD, ALS, MS, and CJD.⁶¹ Considering the widespread prevalence of HCoVs, even mild or moderate neurological effects could have profound public health implications, thereby underscoring the need for long-term surveillance and investigation.

Despite the growing recognition of the neurotoxic potential of HCoVs, there remains significant gaps in our understanding due to technical challenges, limited access to infected human brain tissues, and the inherently prolonged nature of neurological research. Nevertheless, emerging evidence supports several plausible mechanisms linking HCoV infections to neurodegeneration, which include protein aggregation, glial and microglial activation, blood-brain barrier disruption, oxidative stress, and neuroinflammation.⁶⁹ Notably, recent findings have revealed that the SARS-CoV-2 S-protein may directly interact with Aβ and αSyn, potentially promoting their co-aggregation.¹⁷ This raises concerns about whether viral infections can be catalysts for pathological protein misfolding, leading to the acceleration of neurodegenerative processes. Previous studies have shown that the S-protein can bind to Aβ fibrils, enhancing their deposition while influencing αSyn aggregation, which is a hallmark of PD.⁶³,⁶⁴ Moreover, SARS-CoV-2 induces tau hyperphosphorylation and impairs autophagic clearance mechanisms, further worsening proteinopathy-related neurodegeneration.⁶²

The neuronal impacts of COVID-19, such as the appearance of a misfolded, aggregated amyloid fibril state in neuron cells, indicate their resemblances with dementia. Thus, we proposed an essential molecular mechanism. Specifically, the existence of cytotoxic amyloid aggregates (oligomers, protofibrils) from SARS-CoV S-proteins may promote neurodegeneration.¹⁷,⁷⁹,⁸⁰ Further research on the long-term neurological consequences of HCoV infections should be conducted. Advancing our understanding of these mechanisms will be essential for the development of targeted therapeutics that reduce neuroinflammatory damage and inhibit disease progression. Moreover, recognizing and addressing neurological manifestations in viral infections should be a priority in clinical practice. This is because these symptoms may significantly influence prognosis and require individualized treatment strategies. This study emphasized a growing body of evidence linking HCoVs to neurodegenerative disorders, thereby urging the scientific and medical communities to integrate these findings into diagnostic, therapeutic, and preventive frameworks. By elucidating the interplay between viral proteins and pathological aggregates such as Aβ and αSyn, we may uncover novel therapeutic targets that could decrease the long-term burden of virus-induced neurodegeneration.
410 ACKNOWLEDGMENTS

411 The authors acknowledge funding in part by JSPS KAKENHI, grant number 23H03852
412 to K.M.

413 AUTHOR CONTRIBUTIONS

414 CRediT: T.-H.-V.N.—conceptualization, writing-original draft; F.R.—methodology and
415 conceptualization; K.M.—conceptualization, supervision, writing-review and editing. The
416 manuscript was written based on the contributions of all authors. All authors have
417 approved the final version of the manuscript.

418 DECLARATION OF INTERESTS

419 The authors declare no competing interests.

420 DATA AVAILABILITY STATEMENT

421 This is not applicable for this review.

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<figure><img src="image_2.png" /><figcaption>**Figure 1.** Structure (upper) and sequence (lower) comparisons between HCoV proteins and amyloidogenic proteins. (A) Aβ (green, PDB ID: 2NAO) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (B) αSyn (pink, PDB ID: 1XQ8) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (C) tau</figcaption></figure>
766 (purple, PDB ID: 7UPE) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (D) TDP-43 (gray, PDB ID: 7KWZ) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (E) HuPrP (yellow, PDB ID: 5YJ5) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (F) tau first intermediate (purple, PDB ID: 8PPO) + SARS-CoV-2 S-protein (blue, PDB ID: 6VXX), (G) TDP-43 (gray, PDB ID: 4BS2) + SARS-CoV-1 S-protein receptor binding domain (green, PDB ID: 2GHV), (H) HuPrP (yellow, PDB ID: 5YJ5) + SARS-CoV-1 S-protein receptor binding domain (green, PDB ID: 2GHV), and (I) TDP-43 (gray, PDB ID: 4BS2) + MERS-CoV S-protein (yellow, PDB ID: 5X5F). Sequence comparison and structural docking were conducted by Clustal Omega (https://www.ebi.ac.uk/) and Waals (Altif Laboratories), respectively. The areas around the homologous sequence (upper: amyloid, lower HCoV) are presented. The symbols below the sequences highlighted in colours indicate similarity levels. *, perfect match (all sequences have the same amino acid); ., strong similarity (conservative substitution: similar amino acids); ,, weak similarity (semi-conservative substitution: somewhat similar amino acids).
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<table><caption>Table 1. Neuropathological impact of HCoVs on neurodegenerative diseases</caption><thead><tr><th>HCoV type</th><th>Neuroinvasive potential</th><th>Associated neurodegenerative diseases</th><th>Mechanism</th><th>Experimental evidence</th><th>Year</th><th>Ref.</th></tr></thead><tbody><tr><td>HCoV-NL63</td><td>Low</td><td>Limited evidence for neurodegeneration</td><td>Primarily respiratory, rare CNS involvement</td><td>Few reports of encephalitis in pediatric cases</td><td>2006</td><td>11</td></tr><tr><td>HCoV-HKU1</td><td>Low</td><td>No confirmed link to neurodegeneration</td><td>Primarily respiratory, limited neurotropism</td><td>No substantial neuropathological evidence</td><td>2005</td><td>12</td></tr><tr><td>HCoV-229E</td><td>Moderate</td><td>AD, PD</td><td>Potential neuroinflammation and disruption of synaptic function</td><td>Detected in the AD and PD brains</td><td>2000</td><td>18</td></tr><tr><td>HCoV-OC43</td><td>High</td><td>AD, PD, and MS</td><td>Persistent viral RNA in neurons, demyelination, and microglial activation</td><td>Induces chronic demyelination in mouse models</td><td>2006</td><td>39</td></tr><tr><td>MERS-CoV</td><td>High</td><td>Possible association between AD and ALS</td><td>Severe neuroinflammation, neuronal death, BBB disruption</td><td>Reports of cognitive impairment and encephalopathy in survivors</td><td>2015</td><td>28</td></tr><tr><td>SARS-CoV1</td><td>High</td><td>AD, PD</td><td>Direct neuronal infection, neuroinflammation, ACE2 downregulation</td><td>Found in the brain tissue of patients with infection; worsened neurodegeneration in animal models</td><td>2005</td><td>24</td></tr><tr><td></td><td>Very high</td><td>AD, PD</td><td>Spike protein interaction with Aβ, αSyn, cytokine storms, and neuroinflammation; COVID-19 causing demyelination and cytotoxic aggregates of peptides</td><td>Accelerates neurodegeneration</td><td>2020</td><td>14</td></tr><tr><td>SARS-CoV2</td><td>Very high</td><td>ALS</td><td>Directly affecting the CNS, PNS; protein aggregation</td><td>Express neuromusculoskeletal symptoms</td><td>2020</td><td>57</td></tr><tr><td></td><td>Very high</td><td>CJD</td><td>Neuroinflammation and protein misfolding processes</td><td>Induces prion disease progression and prion-related protein aggregation</td><td>2023</td><td>56</td></tr></tbody></table>

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<table><caption>Table 2. Neuropathological impact of HCoVs on amyloid aggregation</caption><thead><tr><th>HCoV</th><th>Amyloid</th><th>Testing method</th><th>Impact/characteristics</th><th>Year</th><th>Ref.</th></tr></thead><tbody><tr><td>SARS-CoV-2 S-protein (Spike532, Spike601)</td><td>Aβ</td><td>Thioflavin T (Th-T) assay, transmission electron microscopy (TEM), circular dichroism (CD), molecular docking (MD), cell-based toxicity assays</td><td>Promotes Aβ aggregation, potentially accelerating AD progression</td><td>2023</td><td>66</td></tr><tr><td>SARS-CoV-2 S-protein (Spike1058)</td><td>Aβ</td><td>Th-T assay, TEM, SPR, Zebrafish toxicity assays</td><td>Promotes Aβ aggregation and cytotoxicity and delays the hatching and survival of zebrafish embryos</td><td>2023</td><td>67</td></tr><tr><td>SARS-CoV-2 S-protein</td><td>αSyn</td><td>TEM, atomic force microscopy (AFM), Western blot analysis, immunofluorescence staining, MD</td><td>Facilitates αSyn aggregation, potentially worsening the PD pathology</td><td>2022</td><td>63</td></tr><tr><td>SARS-CoV-2 S-protein (SK9)</td><td>αSyn</td><td>Th-T assay, AFM, CD, SDS-PAGE</td><td>Facilitates αSyn structural stability and aggregation</td><td>2024</td><td>69</td></tr><tr><td>SARS-CoV-2 S-protein</td><td>Tau</td><td>Western blot analysis, mass spectrometry, fluorescence resonance energy transfer, Cryo-EM</td><td>Enhances the abnormal phosphorylation of Tau, contributing to AD</td><td>2023</td><td>62</td></tr><tr><td>SARS-CoV-2 S-protein S1 domain</td><td>TDP-43</td><td>Immunohistochemistry, ELISA, mass spectrometry, RNA sequencing</td><td>Induces TDP-43 aggregation, potentially linked to ALS and FTD</td><td>2021</td><td>68</td></tr><tr><td>SARS-CoV-2 S-protein (Spike532)</td><td>HuPrP</td><td>Fluorescence polarization, SPR, mass spectrometry</td><td>Possible association with CJD via the cross-seeding mechanisms</td><td>2021</td><td>68</td></tr></tbody></table>

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