Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-beta (A beta) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by A beta overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-A beta MAbs might promote the removal of early A beta accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing A beta (1-11) was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early A beta plaque formation. MAbs reduce the offspring's cortical A beta levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the Fc gamma R1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early A beta deposition, as occurs in EOAD and DS. Illouz et al vaccinated wildtype female mice against human Amyloid-beta (A beta) prior to them being bred with 5xFAD males, which model A beta deposition, as occurs in Alzheimer's Disease (AD) and Down's syndrome (DS). The resultant offspring had reduced cortical A beta levels and milder memory deficits, up to 4 months after antibodies were no longer detectable, due to a long term shift in microglial phenotype. This study demonstrates that maternal immunization can alleviate cognitive decline and pathology associated with AD and DS.