Intracerebral propagation of Alzheimer's disease: Strengthening evidence of a herpes simplex virus etiology

Abstract

Background A faulty human protein, abnormally phosphorylated tau, was recently publicized to spread “like a virus” from neuron to neuron in Alzheimer patients' brains. For several decades, we have been amassing arguments showing that herpes simplex virus type 1 (HSV-1), not p-tau, propagates this inter-neuronal, trans-synaptic pathological cascade. Methods We reiterate convincing data from our own (and other) laboratories, reviewing the first anatomic foothold neurofibrillary tangles gain in brainstem and/or entorhinal cortex; the chronic immunosurveillance cellularity of the trigeminal ganglia wherein HSV-1 awakens from latency to reactivate; the inabilities of p-tau protein's physical properties to promote it to jump synapses; the amino-acid homology between human p-tau and VP22, a key target for phosphorylation by HSV serine/threonine-protein kinase UL13; and the exosomic secretion of HSV-1-infected cells' L-particles, attesting to the cell-to-cell passage of microRNAs of herpes viruses. Results The now-maturing construct that reactivated HSV-1 best accounts for the intracerebral propagation of AD changes in the human brain should at last seem highly attractive. This hypothesis might even explain statins' apparent mechanism in some studies for lowering AD incidence. Conclusion Provided that funding agencies will quickly ignite a new realm of investigation, the rejuvenated enthusiasm for testing this optimistic construct holds incalculable potential for rapid, efficacious clinical application, through already available and relatively safe anti-viral therapeutics.

The Role of PICALM in Alzheimer’s Disease

“…Particularly, compelling pieces of evidence have been strongly suggestive of the association between herpes simplex virus 1 (HSV-1) and AD [121][122][123][124][125]. Licastro et al and Carter et al proposed that the presence of susceptibility genes associated with AD (such as PICALM) leads to some vulnerability of HSV-1 invasion to CNS by affecting immune defense ability and viral invasiveness, and thus results in subsequent neuropathological insults, such as neuronal loss, inflammation, and amyloid deposition [126,127], suggesting the causative interaction among genes, pathogens, and the immune system in etiology of sporadic AD.…”

How plausible is a link between HSV-1 infection and Alzheimer’s disease?

“…Great progresses have been made in understanding the components of the pathological lesions observed in the disease, but the knowledge about the mechanisms that trigger the onset of AD is still very limited. Among the different hypotheses that have been presented over the years, a viral involvement has long been suspected to play an important role in the pathogenesis and the progression of this disease [1]. Currently, the most compelling theory is that human herpesviruses, with their high rate of infection in general population, neurotropism and lifelong persistence in neuronal cells, could play a key role in neurodegeneration upon interacting with important characteristics of the host [2].…”

Herpes Simplex Virus Linked to AlzheimerÂ’s Disease

“…AD is pathologically characterized by intracellular neurofibrillary tangles and extracellular senile plaques. While the pathogenesis of AD is still elusive, it is widely recognized that APP plays a central role in the pathogenesis of AD based on the following evidence: i) APP is the precursor to beta-amyloid peptide (Abeta), a main constituent of senile plaques which causes cell death, synaptic defects and memory impairment [4][5][6][7][8][9]; ii) Disruption of APP-mediated axonal transport contributes to the neurodegeneration associated with AD [10]; iii) Aberrant APP phosphorylation results in Abeta production, cell stress and degeneration [10][11][12].RT-PCR studies reveal the existence of HSV-1 DNA in plaques of frontal and temporal cortices in post-mortem brains of both sporadic and familial Alzheimer's disease [13][14][15][16]. The presence of HSV-1 in the brain is considered to be a risk factor for AD in elderly people who carry the apolipoprotein E ε4 allele [17].…”

“…RT-PCR studies reveal the existence of HSV-1 DNA in plaques of frontal and temporal cortices in post-mortem brains of both sporadic and familial Alzheimer's disease [13][14][15][16]. The presence of HSV-1 in the brain is considered to be a risk factor for AD in elderly people who carry the apolipoprotein E ε4 allele [17].…”

“…In addition, HSV-1 infection of human neuronal cell line increases the phosphorylation of tau proteins, the main component of neurofibrillary tangles, one of the hallmarks of AD [28]. A viral kinase, UL13, which phosphorylates HSV-1 VP22, may phosphorylates human tau proteins [16]. Moreover, treatment of HSV-1-infected cells with acyclovir, the main antiviral agent used for treating HSV-1 infection by targeting viral DNA replication, substantially decreases the amount of Abeta and phosphorylated tau protein, two culprits of AD [29].…”