FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease
Date
2022-05-24Author
Lee, Annie J.
Raghavan, Neha S.
Bhattarai, Prabesh
Siddiqui, Tohid
Sariya, Sanjeev
Reyes‑Dumeyer, Dolly
Flowers, Xena E.
Cardoso, Sarah A. L.
De Jager, Philip L.
Bennett, David A.
Schneider, Julie A.
Menon, Vilas
Wang, Yanling
Lantigua, Rafael A.
Medrano, Martin
Rivera, Diones
Jimenez‑Velazquez, Ivonne Z.
Kukull, Walter A.
Brickman, Adam M.
Manly, Jennifer J.
Tosto, Giuseppe
Kizil, Caghan
Vardarajan, Badri N.
Mayeux, Richard
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Show full item recordAbstract
Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle
age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs
and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568
patients and 8101 controls identified FMNL2 (p = 6.6 × 10– 7). A significant increase in FMNL2 expression was observed
in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau
deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity
in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown
of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice
also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based
on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling
gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk
factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular
mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.
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