Spatial and planar profiling of Rac1/Cdc42 signaling in Alzheimer's disease brain.

Autor:	Akhtar SN; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.; Department of Chemistry and Biochemistry, The University of South Carolina, Columbia, SC, USA., Tran TD; Department of Psychology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC, USA.; The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative Diseases Research, Brody School of Medicine, East Carolina University, Greenville, NC, USA., Chen YH; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.; Department of Chemistry and Biochemistry, The University of South Carolina, Columbia, SC, USA.; Center for Neurotherapeutics, College of Arts and Sciences, The University of South Carolina, Columbia, SC, USA., Lu Q; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.; Department of Chemistry and Biochemistry, The University of South Carolina, Columbia, SC, USA.; The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative Diseases Research, Brody School of Medicine, East Carolina University, Greenville, NC, USA.; Center for Neurotherapeutics, College of Arts and Sciences, The University of South Carolina, Columbia, SC, USA.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2024 Dec; Vol. 102 (3), pp. 670-682. Date of Electronic Publication: 2024 Nov 29.
DOI:	10.1177/13872877241291076
Abstrakt:	Background: A neuropathogenic hallmark of Alzheimer's disease (AD) is loss of neuronal synapses in selective brain regions. Small GTPases Rac1 and Cdc42, critical modulators of synaptic architecture and remodeling, are dysregulated in AD brains and are potential AD therapeutic targets. However, the exact contribution of their signaling to AD is still not clear. Objective: We intend to investigate the hypothesis that Rac1/Cdc42 activity changes in a spatial and planar dependent manner in relation to AD. Methods: We applied anti-pRac/Cdc42 (Serine 71 phosphorylation), which recognizes an inactive form of Rac1/Cdc42, and anti-pPAK (Threonine 423 phosphorylation), which detects the active PAK, a positive downstream effector of Rac1/Cdc42 signaling. For this study, triple transgenic mouse model (3xTg-AD) brain and human AD brain samples were used. Results: pRac/Cdc42 expression was decreased in 3xTg-AD mouse cortex while pPAK expression increased compared to wild-type mouse cortex. Immunostaining of mouse brain serial sections revealed increased pRac/Cdc42 expression in the rostral region, decreased expression in the caudal region, and pPAK showed an overall opposite trend of pRac/Cdc42. There was also a brain plane specific nuclear to cytoplasmic redistribution of pRac/Cdc42. Human non-dementia and AD cortex and cerebellum showed differential expressions for pRac/Cdc42, Rac1, and Cdc42. Mouse whole transcriptome analysis demonstrated spatial dependent expression of Rac1/Cdc42 signaling-associated genes in neuronal and non-neuronal (astrocyte) populations of 3xTg-AD hippocampi. Conclusions: Rac1/Cdc42 signaling is dysregulated in both 3xTg-AD mouse and AD human brain and Rac1/Cdc42 activity level changes along the spatial and planar dimensions. Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Databáze:	MEDLINE
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