title: Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in Alzheimer's disease.
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.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Perez
authors.forename: Damianka P
authors.initials: DP
authors.lastname: Getova
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Scott E
authors.initials: SE
authors.lastname: Counts
authors.forename: Changiz
authors.initials: C
authors.lastname: Geula
authors.forename: Laurent
authors.initials: L
authors.lastname: Desire
authors.forename: Severine
authors.initials: S
authors.lastname: Coutadeur
authors.forename: Helene
authors.initials: H
authors.lastname: Peillon
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D020532:Basal Nucleus of Meynert / Q000378:metabolism*; D002102:Cadaver; D051243:Caveolin 2 / Q000235:genetics; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics; D006801:Humans; D008297:Male; D012326:RNA Splicing / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D002787:Sterol Esterase / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D016875:tau Proteins
chemical_list: C495544:CAV2 protein, human; D051243:Caveolin 2; C534984:GNB4 protein, human; D044387:GTP-Binding Protein beta Subunits; C107953:RAC1 protein, human; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D016875:tau Proteins; C503451:LIPA protein, human; D002787:Sterol Esterase; D020830:rac1 GTP-Binding Protein