Abstract
Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.
Highlights
Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy
Reported AD top markers, APOE single nucleotide polymorphism (SNP) rs42935815, TOMM40 SNP rs207565015, APOC1 SNP rs1272105116, and rs117028417 on FAM222A were found in one module (Fig. 1, Supplementary Figs. 2, 3 and Supplementary Table 1), which consists of five regions of interest (ROI) including left hippocampus, right hippocampus, basal forebrain, entorhinal area, and planum polare, brain areas we know are affected by AD17–19 and well predict AD (Supplementary Fig. 4)
SNP rs117028417 had a minor allele A with positive effects for all 5 ROIs in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (P = 1.95 × 10−8 for cross-phenotype association analysis (CPASSOC) analysis; Supplementary Table 2), and was further validated to be associated with the mean volume of hippocampus, one of the earliest affected brain regions in AD, in the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium cohort comprising magnetic resonance imaging (MRI) images of
Summary
Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. 1234567890():,; Alzheimer’s disease (AD), the leading cause of dementia named for Dr Alois Alzheimer, is characterized by pathologic hallmarks amyloid plaques and neurofibrillary tangles, and accompanied by other prominent pathological changes such as progressive atrophy of the brain, neuropil threads, dystrophic neurites, granulovacuolar degeneration, Hirano bodies, and cerebrovascular amyloid[1]. In support of the dominant amyloid cascade hypothesis suggesting Aβ deposition in the brain as the primary cause, a number of AD-associated genes are enriched in the APP processing pathway, and involved in Aβ overproduction and amyloid plaque deposition though their encoded proteins are usually not directly associated with amyloid plaques
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