Abstract Body

Among the growing number of genes associated with risk for Alzheimer’s disease (AD), the fastest growing group are involved with innate immunity. We reported the first AD-associated innate immune AD gene, CD33, in 2008, which was followed by the report of association of AD with TREM2. Using knockouts of these genes in 5XFAD mice, we have demonstrated these two genes to confer opposite effects on microglial activation. While knockout of CD33 led to increased microglial clearance of Aβ and improved cognitive performance, TREM2 knockout had opposite effects in 5XFAD mice. Another innate immune AD-associated gene, INPP5D, encodes SHIP1, an adaptor for TYROBP (DAP12) in the TREM2 transduction pathway. In preliminary studies, knockdown of INPP5D in BV2 murine microglia led to increased phagocytosis of Aβ, increased autophagy, and increased lysosomal compartment size. In an extension of the role of innate immunogenetics in AD, we have reported that Aβ is an antimicrobial peptide that can protect against microbes such as viruses, bacteria, and fungus. Binding of Aβ to microbes rapidly nucleates amyloid depositon, which entraps the microbe, affording host cell defense. Preliminary studies indicate that both viral infection and Aβ deposition trigger neurofibrillary tangles, which physically block neurotropic spread of viruses. In view of these findings, we propose that AD neuropathology is an evolutionarily-conserved, orchestrated set of innate immune responses that evolved to protect the brain against infection. We further posit that AD-associated genetic risk variants evolved during epidemics of encephalitis and meningitis, owing to their ability to afford protection against brain infection.