Anti-Viral Agents in Neurodegenerative Disorders: New Paradigm for Targeting Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease affecting geriatric populations for which several causes have been proposed. These include a relationship with known pathogens although the exact nature of such a relationship remains uncertain. Herpes simplex virus-1 has been proposed as potential cause of AD because of its ability to form ß amyloid(Aß) and neurofibrillary tangles due to tau hyperphosphorylation and action of beta & gamma secretase on amyloid precursor protein(APP) together with genetic association with apolipoprotein-E4(ApoE-Ɛ4), which points out to latent Herpes Simplex virus-1 as an agent causing AD. There are numerous studies that linked HSV-1 with AD like anti-HSV-1 IgM antibodies, nectin-2, heme oxygenase-1, phosphorylated eukaryotic initiation factor-2A, caspase-8 and nucleus-specific alteration of raphe neurons. Various possible mechanisms by which HSV-1 might lead to development of AD such as ApoE, ß-amyloid, tau phosphorylation, inflammation and oxidative stress are also discussed. Thus, this review discusses patent information and a strong relationship between latent HSV-1 and AD and also proposes antiviral therapy for AD.

Alzheimer's Gone Viral: Could Herpes Simplex Virus Type-1 Be Stealing Your Memories?

“…An increase in the intracellular levels of amyloid-β and a decrease in APP and P-tau follow [4,17]. This further accelerates the deposition of amyloid plaques and NFTs, which are the main components of AD [13,17]. HSV1 infection induces early upstream events that eventually lead to Aβ deposition and P-tau and thus superimpose our speculation that HSV1 is a possible risk factor for AD [39].…”

“…Thus, a vicious cycle of uncontrolled neural inflammation and neurodegeneration ensues [7,11]. Thus, data show that reactivation of HSV1 infection causes AD [12][13]17,[20][21]25,29,42,45].…”

“…AD is a progressive neurodegenerative disorder of multifactorial etiology, causing irreversible pathological changes in the brain [4,7,[11][12][13][14][15][16]. Macroscopically, this appears as atrophy of the brain starting from the locus coeruleus, entorhinal cortex, and hippocampus of medial temporal lobes and gradually affecting the inferolateral temporal cortex and nucleus basalis of Meynert [2,[10][11].…”

“…Aβ40 and Aβ42 primarily form the classical amyloid plaques seen in AD. The non-amyoidogenic pathway is made up of α and γ secretase.Key: HSV1 -Herpes simplex virus type-1, APP and AβPP -Amyloid-beta precursor protein, AICD -APP intracellular domain, BACE1 -Beta site APP cleaving enzyme References:[2,7,11,13,[15][16][17][18]29,36,38,41]…”

“…HSV1 reactivation, measured by anti-HSV1 immunoglobulin M (IgM) antibodies, is associated with an increased risk of developing AD(Table 3)[3,7,[13][14][15][16][17][20][21][22]25,29,42,48].The study included 3,432 elderly patients (53.9% women, mean age at inclusion 62.7 ± 14.4 years) with an average follow-up time of 11.3 years. They observed a baseline increased serum level of anti-HSV IgM antibodies associated with an increased risk of developing AD (Hazard ratio: 1.96, p = 0.012).…”