Abstract Body

Over the past decade, an increasing number of innate immune genes have been associated with Alzheimer’s disease (AD). We reported the first innate immune gene associated with AD (CD33) based on a genome-wide association study (GWAS) employing the NIMH AD family sample (Bertram et al., 2008). This association was confirmed three years later in a case-control GWAS (Naj et al. 2011). TREM2 was reported as a the second AD-associated innate immune gene. We have shown knockout of CD33 or TREM2 genes in 5XFAD mice have opposite effects on microglial activation: Knockout of CD33 increases microglial phagocytosis of Aβ and ameliorates cognition, while TREM2 knockout had opposite effects (Griciuc et al, 2019). Double knockout of CD33 and TREM2 in 5XFAD mice leads to a TREM2 knock out phenotype suggesting TREM2 functions downstream of CD33. We have also shown that Aβ is an antimicrobial peptide in the brain’s innate immune system. Using 3D human neural-glial cell cultures and AD mouse models, we showed that viruses and bacteria rapidly" seed" Aβ plaques. Viral infection and Aβ deposition also trigger tangle formation and neurodegeneration in 3D neural culture models, and inflammation in AD mouse models. Based on these data, the late Dr. Rob Moir and I proposed “The Antimicrobial Protection Hypothesis of Alzheimer’s Disease”, which posits that AD neuropathology comprises an evolutionarily-conserved, orchestrated set of immune responses to protect the brain against infection. Furthermore, we posit that AD-associated genes have been evolutionarily conserved given their ability to bolster the AD neuropathology as an innate immune defense in the brain.