Regional Selectivity of rab5 and rab7 Protein Upregulation in Mild Cognitive Impairment and Alzheimer's Disease

Article type: Research Article

Authors: Ginsberg, Stephen D.^{a; b; c; *} | Mufson, Elliott J.^d | Counts, Scott E.^d | Wuu, Joanne^e | Alldred, Melissa J.^{a; b} | Nixon, Ralph A.^{a; b; f} | Che, Shaoli^{a; b}

Affiliations: [a] Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA | [b] Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA | [c] Department of Physiology & Neuroscience, New York University Langone Medical Center, New York, NY, USA | [d] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA | [e] Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA | [f] Department of Cell Biology, New York University Langone Medical Center, New York, NY, USA

Correspondence: [*] Correspondence to: Stephen D. Ginsberg, Ph.D., Center for Dementia Research, Nathan Kline Institute, New York University Langone Medical Center, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel.: +1 845 398 2170; Fax: +1 845 398 5422; E-mail: ginsberg@nki.rfmh.org

Abstract: Endocytic alterations are one of the earliest changes to occur in Alzheimer's disease (AD), and are hypothesized to be involved in the selective vulnerability of specific neuronal populations during the progression of AD. Previous microarray and real-time quantitative PCR experiments revealed an upregulation of the early endosomal effector rab5 and the late endosome constituent rab7 in the hippocampus of people with mild cognitive impairment (MCI) and AD. To assess whether these select rab GTPase gene expression changes are reflected in protein levels within selectively vulnerable brain regions (basal forebrain, frontal cortex, and hippocampus) and relatively spared areas (cerebellum and striatum), we performed immunoblot analysis using antibodies directed against rab5 and rab7 on postmortem human brain tissue harvested from cases with a premortem clinical diagnosis of no cognitive impairment (NCI), MCI, and AD. Results indicate selective upregulation of both rab5 and rab7 levels within basal forebrain, frontal cortex, and hippocampus in MCI and AD, which also correlated with Braak staging. In contrast, no differences in protein levels were found in the less vulnerable cerebellum and striatum. These regional immunoblot assays are consistent with single cell gene expression data, and provide protein-based evidence for endosomal markers contributing to the vulnerability of cell types within selective brain regions during the progression of AD.

Keywords: Basal forebrain, cerebellum, endosome, frontal cortex, hippocampus, mild cognitive impairment, rab GTPase, selective vulnerability, striatum

DOI: 10.3233/JAD-2010-101080

Journal: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 631-639, 2010