FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease
Tingxiang Yan, Jingjing Liang, Ju Gao, Luwen Wang, Hisashi Fujioka, The Alzheimer Disease Neuroimaging Initiative, Michael W. Weiner, Norbert Schuff, Howard J. Rosen, Bruce L. Miller, David C. Perry, Paul Aisen, Arthur W. Toga, Gustavo Jiménez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Arthur W. Toga, Karen Crawford, Scott Neu, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, Paul Aisen, Ronald Petersen, Clifford R. Jack, Matt A. Bernstein, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Prashanthi Vemuri, David T. Jones, Kejal Kantarci, Chad Ward, Sara S. Mason, Colleen S. Albers, David S. Knopman, Kris Johnson, Neill R. Graff‐Radford, Francine Parfitt, Kim Poki-Walker, William J. Jagust, Susan Landau, John Q. Trojanowki, Leslie M. Shaw, Jason Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Virginia Lee, Magdalena Korecka, Michal Figurski, Laurel Beckett, Danielle Harvey, Charles DeCarli, Evan Fletcher, Pauline Maillard, John Olichney, Owen Carmichael, Robert C. Green, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Andrew J. Saykin, Tatiana Foroud, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, John C. Morris, Marc Raichle, David M. Holtzman, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor‐Reinwald, Beau M. Ances, David Winkfield, Maria Carroll, Angela Oliver, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Lew Kuller, Chet Mathis, Oscar L. López, MaryAnn Oakley, Donna M. Simpson
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.