Alzheimer's disease plaques and tangles: Cemeteries of a Pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction.
Plaques and tangles are highly and significantly enriched in herpes simplex (HSV-1) binding proteins (by 11 and 15 fold respectively (P<4.47466E-39) and 132/341 (39%) of the known HSV-1 binding partners or associates are present in these structures. The classes involved include the majority (63-100%) of the known HSV-1 host protein carriers and receptors, 85-91% of the viral associated proteins involved in endocytosis, intracellular transport and exocytosis and 71% of the host proteins associated with the HSV-1 virion. The viral associated proteins found in plaques or tangles trace out a complete itinerary of the virus from entry to exocytosis and the virus also binds to plaque or tangle components involved in apoptosis, DNA transcription, translation initiation, protein chaperoning, the ubiquitin/proteasome system and the immune network. Along this route, the virus deletes mitochondrial DNA, as seen in Alzheimer's disease, sequesters the neuroprotective peptide, ADNP, and interferes with key proteins related to amyloid precursor protein processing and signalling as well as beta-amyloid processing, microtubule stability and tau phosphorylation, the core pathologies of Alzheimer's disease. Amyloid-containing plaques or neurofibrillary tangles also contain a large number of complement, acute phase and immune-related proteins, and the presence of these pathogen defence related classes along with HSV-1 binding proteins suggests that amyloid plaques and tangles represent cemeteries for a battle between the virus and the host's defence network. The presence of the complement membrane attack complex in Alzheimer's disease neurones suggests that complement mediated neuronal lysis may be a consequence of this struggle. HSV-1 infection is known to increase beta-amyloid deposition and tau phosphorylation and also results in cortical and hippocampal neuronal loss, cerebral shrinkage and memory deficits in mice. This survey supports the contention that herpes simplex viral infection contributes to Alzheimer's disease, in genetically predisposed individuals. Genetic conditioning effects are likely to be important, as all of the major risk promoting genes in Alzheimer's disease (apolipoprotein E, clusterin, complement receptor 1 and the phosphatidylinositol binding clathrin assembly protein PICALM), and many lesser susceptibility genes, are related to the herpes simplex life cycle. 33 susceptibility genes are related to the immune system. Vaccination or antiviral agents and immune suppressants should therefore perhaps be considered as viable therapeutic options, prior to, or in the early stages of Alzheimer's disease.[1]References
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