Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

Eimer, William A.; Kumar, Deepak Kumar Vijaya; Shanmugam, Nanda Kumar N.; Rodríguez, A; Mitchell, Teryn; Washicosky, Kevin J.; György, Bence; Breakefield, Xandra O.; Tanzi, Rudolph E.; Moir, Robert D.

doi:10.1016/j.neuron.2018.11.043

Cited by 168 publications

(198 citation statements)

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“…Moreover, herpes viruses, which are neurotropic, might directly infect and damage selected brain areas in genetically susceptible elderly, contributing to neurodegenerative mechanisms [5], and herpes DNA has been indeed found in AD brains [4,8,25]. [8,29,30]. Other pathogens have been implicated in the clinical history of AD [31], and chronic infections are emerging risk factors for the disease [32].…”

Section: Discussionmentioning

confidence: 99%

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer’s Disease

Romagnoli

Porcellini

Carbone

et al. 2020

IJMS

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Among environmental factors likely associated with Alzheimer's disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency.

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Section: Discussionmentioning

confidence: 99%

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer’s Disease

Romagnoli

Porcellini

Carbone

et al. 2020

IJMS

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“…The amyloid-beta protein precursor (A␤PP) plays a central role in this aspect of neuroplasticity [13]. A considerable amount of evidence has related A␤PP to AD [22], including a relationship between its A␤ product and APOE genotype [23]. A␤PP can be cleaved either by the ␣-secretase, which leads to increased local synapse production and prevents formation of the synaptotoxic A␤ molecule or by the ␤-secretase, followed by ␥-secretase, which leads to the removal of the affected synapse [22].…”

Section: Introductionmentioning

confidence: 99%

“…A considerable amount of evidence has related A␤PP to AD [22], including a relationship between its A␤ product and APOE genotype [23]. A␤PP can be cleaved either by the ␣-secretase, which leads to increased local synapse production and prevents formation of the synaptotoxic A␤ molecule or by the ␤-secretase, followed by ␥-secretase, which leads to the removal of the affected synapse [22]. The control of the delicate balance between synapse creation and destruction is critical for learning and involves numerous mechanisms, with a positive neuronal action culminating in activation of the ␣-secretase, while activation failure leads Mixed APOE4 allele is associated with psoriasis severity 4 carriers were significantly more common in patients with severe psoriasis compared to controls (p = 0.003) and to non-severe psoriasis (p = 0.017)…”

Section: Introductionmentioning

confidence: 99%

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Smith

Ashford

Perfetti³

2019

JAD

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Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

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“…Infections by herpesviruses induce similar hallmark features observed in AD, including Aβ production, phosphorylation of Tau, oxidative stress, and neuroinflammation . Aβ peptides can act as antimicrobial peptides (AMP) against some common microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV‐1 oxidative stress, and dysfunctional lysosome .…”

Section: Introductionmentioning

confidence: 99%

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment

Qin

2019

Journal of Medical Virology

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Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P-tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV-1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P-tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE-ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti-herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.

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Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

Cited by 168 publications

References 0 publications

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer’s Disease

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer’s Disease

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment

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