Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal f...

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Published in:Pharmaceutics 2022-06, Vol.14 (7), p.1354
Main Authors: Ganne, Akshatha, Balasubramaniam, Meenakshisundaram, Griffin, W. Sue T., Shmookler Reis, Robert J., Ayyadevara, Srinivas
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimer’s disease (AD)
Bacteria
Biomarkers
Dementia
E coli
Eggs
glial fibrillary acidic protein (GFAP)
Huntingtons disease
Kinases
Neuroblastoma
Oxidation
Parkinson's disease
post-translational modification (of proteins)
protein aggregation
protein phosphorylation
Proteins
Worms
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Summary:Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer’s disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [ε4, ε4] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington’s disease) and of Alzheimer’s-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14071354