FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease

Authors

Tingxiang Yan, CASE School of Medicine
Jingjing Liang, Case Western Reserve University
Ju Gao, CASE School of Medicine
Luwen Wang, CASE School of Medicine
Hisashi Fujioka, Case Western Reserve University
Michael W. Weiner, University of California, San Francisco
Norbert Schuff, University of California, San Francisco
Howard J. Rosen, University of California, San Francisco
Bruce L. Miller, University of California, San Francisco
David Perry, University of California, San Francisco
Paul Aisen, University of Southern California
Paul Aisen, University of Southern California
Arthur W. Toga, University of Southern California
Gustavo Jimenez, University of Southern California
Michael Donohue, University of Southern California
Devon Gessert, University of Southern California
Kelly Harless, University of Southern California
Jennifer Salazar, University of Southern California
Yuliana Cabrera, University of Southern California
Sarah Walter, University of Southern California
Lindsey Hergesheimer, University of Southern California
Arthur W. Toga, University of Southern California
Karen Crawford, University of Southern California
Scott Neu, University of Southern California
Lon S. Schneider, University of Southern California
Sonia Pawluczyk, University of Southern California
Mauricio Becerra, University of Southern California
Liberty Teodoro, University of Southern California
Bryan M. Spann, University of Southern California
Ronald Petersen, Mayo Clinic
Clifford R. Jack, Mayo Clinic
Matthew Bernstein, Mayo Clinic

Document Type

Article

Publication Date

12-1-2020

Journal

Nature Communications

Volume

11

Issue

1

URL with Digital Object Identifier

10.1038/s41467-019-13962-0

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.