Alzheimer's disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner

Abstract

Herpes simplex is implicated in Alzheimer's disease and viral infection produces Alzheimer's disease like pathology in mice. The virus expresses proteins containing short contiguous amino acid stretches (5-9aa "vatches" = viralmatches) homologous to APOE4, clusterin, PICALM, and complement receptor 1, and to over 100 other gene products relevant to Alzheimer's disease, which are also homologous to proteins expressed by other pathogens implicated in Alzheimer's disease. Such homology, reiterated at the DNA level, suggests that gene association studies have been tracking infection, as well as identifying key genes, demonstrating a role for pathogens as causative agents. Vatches may interfere with the function of their human counterparts, acting as dummy ligands, decoy receptors, or via interactome interference. They are often immunogenic, and antibodies generated in response to infection may target their human counterparts, producing protein knockdown, or generating autoimmune responses that may kill the neurones in which the human homologue resides, a scenario supported by immune activation in Alzheimer's disease. These data may classify Alzheimer's disease as an autoimmune disorder created by pathogen mimicry of key Alzheimer's disease-related proteins. It may well be prevented by vaccination and regular pathogen detection and elimination, and perhaps stemmed by immunosuppression or antibody adsorption-related therapies.

Figure 1

The BLAST result for HSV-1 proteins (translated viral genome versus human proteins) using the filter “lipoprotein.” The repetitive patterns in the pictogram reflect homology with a number of different lipoprotein receptors located on different chromosomes, as shown in the table.

Figure 2

The B cell and T cell immunogenicity profile for the beta-amyloid peptide. According to the servers, antigenicity values of >0.35 (B cell) or 0.5 (T cell) are considered immunogenic. The sequences of herpes simplex viral proteins that align with beta-amyloid are shown. Space: non-identical amino acid; +: conserved amino acid with similar physicochemical properties. Viruses and phages containing the VGGVV sequence, which has been used as an epitope to label beta-amyloid in Alzheimer's disease, are also shown.

Figure 3

The B cell and T cell immunogenicity profile for the tau protein. The sequences of herpes simplex viral proteins that align with tau are shown. Space: non-identical amino acid; +: conserved amino acid with similar physicochemical properties.