Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in alzheimer's disease

Sylvia E. Perez*, Damianka P. Getova, Bin He, Scott E. Counts, Changiz Geula, Laurent Desire, Severine Coutadeur, Helene Peillon, Stephen D. Ginsberg, Elliott J. Mufson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75 NTR to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75 NTR and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75 NTR-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75 NTR-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75 NTR-labeled NB neurons compared with Rac1b-negative/p75 NTR-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.

Original languageEnglish (US)
Pages (from-to)526-540
Number of pages15
JournalAmerican Journal of Pathology
Volume180
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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