Alzheimer’s disease: APP, gamma secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, MS4A2, herpes simplex, C.pneumoniae and immunity

The major susceptibility genes identified in Alzheimer’s disease genome-wide association studies (APOE, ABCA7, BIN1, CLU, CD2AP, CD33, CR1, EPHA1, MS4A2 and PICALM), as well as APP and gamma-secretase are involved in the herpes simplex life cycle, or in that of other suspect pathogens (C.Pneumoniae, H.Pylori, C.Neoformans, B. Burgdorferri and P.Gingivalis) or in immune defence. As several of these pathogens can promote beta-amyloid deposition and tau phosphorylation in non-transgenic models, they might be considered as causative agents in the human condition, whose effects are tempered by susceptibility genes. Beta-amyloid is an antimicrobial peptide, and APP and gamma-secretase are highly expressed in dendritic cells, the scouts that present pathogen antigens to immunocompetent cells. Gamma secretase cleaves 21 viral or microbial receptors, including those for the suspect pathogens and the primary role of the amyloid/secretase network may well be related to pathogen disposal, effects which may be abrogated by the presence of beta-amyloid autoantibodies in the elderly. These autoantibodies, as well as those to nerve growth factor and tau, also observed in Alzheimer’s disease, may well in fact be antibodies to pathogens, as there exists a marked homology between the human autoantigens and pathogen proteins. Antibodies to NGF or tau promote beta-amyloid deposition, neurofibrillary tangles or cholinergic neuronal loss, and, with other autoantibodies, such as anti-ATPase, they are potential agents of destruction, whose formation is dictated by sequence homology between pathogen and human proteins, and thus by pathogen strain and human genes. The regular detection and elimination of pathogens in the ageing population might impact significantly upon the incidence of Alzheimer’s disease, and the early selective removal of culpable autoantibodies might offer hope for a cure. Tweet