FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease

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.

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

“…We tested the neuroprotective effect of seven hit MTDLs in an adult zebrafish amyloidosis model, demonstrating AD-like symptoms including synaptic degeneration and blood–brain barrier modulation. − Adult zebrafish brains were treated with 20 μM Aβ42 either alone or in combination with seven hit MTDLs ( 10 , 13 – 16 , 19 , and 49 ), donepezil, and 6 as a negative control at the concentration of 10 μM using cerebroventricular microinjection (CVMI) technique. After 5 days post-injection, immunostaining was performed on telencephalon sections for a synaptic marker using synaptic vesicle glycoprotein 2 (SV2) antibody (Figure A–C).…”

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

“…The neurons survive and integrate into the existing circuitry, suggesting that the zebrafish can be used as a useful experimental model to investigate neuronal regeneration. The mechanisms identified in zebrafish could be used for clinical applications in human brains, as exemplified in recent studies that employed zebrafish as a comparative functional genomics tool for human AD [ 35 , 36 ]. Similarly, the genes associated with AD in humans can be tested for their functionality in the adult zebrafish brain.…”

Microglia associations with brain pericytes and the vasculature are reduced in Alzheimer’s disease

“…This schematic also illustrates our finding that PEM can be found adjacent to pericytes lacking AQP4 positive astrocyte endfeet coverage. It is unknown if astrocyte endfeet coverage is altered in the SFG of AD, but endfeet coverage or function is hypothetically reduced, as suggested by others 68,69 .…”