PUBLICATION
FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease
- Authors
- Lee, A.J., Raghavan, N.S., Bhattarai, P., Siddiqui, T., Sariya, S., Reyes-Dumeyer, D., Flowers, X.E., Cardoso, S.A.L., De Jager, P.L., Bennett, D.A., Schneider, J.A., Menon, V., Wang, Y., Lantigua, R.A., Medrano, M., Rivera, D., Jiménez-Velázquez, I.Z., Kukull, W.A., Brickman, A.M., Manly, J.J., Tosto, G., Kizil, C., Vardarajan, B.N., Mayeux, R.
- ID
- ZDB-PUB-220525-3
- Date
- 2022
- Source
- Acta Neuropathologica 144(1): 59-79 (Journal)
- Registered Authors
- Kizil, Caghan
- Keywords
- Alzheimer’s disease, Blood–brain-barrier, Cerebrovascular risk factors, FMNL2, GWAS, Gliovascular interaction, Human, Mouse, Neurovascular unit, Zebrafish
- MeSH Terms
-
- Alzheimer Disease*/pathology
- Amyloid beta-Peptides/metabolism
- Amyloid beta-Protein Precursor/genetics
- Amyloid beta-Protein Precursor/metabolism
- Amyloidosis*/complications
- Animals
- Brain/pathology
- Disease Models, Animal
- Formins
- Humans
- Mice
- Mice, Transgenic
- Risk Factors
- Zebrafish/metabolism
- PubMed
- 35608697 Full text @ Acta Neuropathol.
Citation
Lee, A.J., Raghavan, N.S., Bhattarai, P., Siddiqui, T., Sariya, S., Reyes-Dumeyer, D., Flowers, X.E., Cardoso, S.A.L., De Jager, P.L., Bennett, D.A., Schneider, J.A., Menon, V., Wang, Y., Lantigua, R.A., Medrano, M., Rivera, D., Jiménez-Velázquez, I.Z., Kukull, W.A., Brickman, A.M., Manly, J.J., Tosto, G., Kizil, C., Vardarajan, B.N., Mayeux, R. (2022) FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease. Acta Neuropathologica. 144(1):59-79.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping