Abbreviations: ac, anterior commissure; AMG, amygdala; Ch4al, cholinergic anterolateral NB portion; Ch4am, cholinergic anteromedial NB portion; Ch4id, cholinergic intermediate-dorsal NB portion; Ch4iv, cholinergic intermediate-ventral NB portion; Fx, fornix; GPe, external globus pallidus; GPi, internal globus pallidus; ic, internal capsule; oc, optic chiasm; Put, putamen nucleus. mmc3.pdf (239K) GUID:?584330D2-4EB6-46EB-A7FD-399526C90878 Supplemental Figure TAS 301 S4 ACC: Schematic illustrations showing the distribution of neurons either dual stained for Rac1b+/p75NTR (red-brown) or singly for p75NTR (green) throughout the rostrocaudal extent of the NB in a representative severe AD case similar to Supplemental Figure S1CS3. GPi, internal globus pallidus; ic, internal capsule; oc, optic chiasm; Put, putamen nucleus. mmc2.pdf (299K) GUID:?260F802C-0F91-423F-86DD-66287DDBD660 Supplemental Figure S3 ACC: Schematic illustrations showing the distribution of neurons either dual stained for Rac1b+/p75NTR (red-brown) or singly for p75NTR (green) throughout the rostrocaudal extent of the NB in a representative mild/moderate AD case similar to Supplemental Figures S1 and S2. The specific level of the basal forebrain is depicted in the small coronal schematic drawings. Each square represents a single cell. Abbreviations: ac, anterior commissure; AMG, amygdala; Ch4al, cholinergic anterolateral NB portion; Ch4am, cholinergic anteromedial NB portion; Ch4id, cholinergic intermediate-dorsal NB portion; Ch4iv, cholinergic intermediate-ventral NB TAS 301 portion; Fx, fornix; GPe, external globus pallidus; GPi, internal globus pallidus; ic, internal capsule; oc, optic chiasm; Put, putamen nucleus. mmc3.pdf (239K) GUID:?584330D2-4EB6-46EB-A7FD-399526C90878 Supplemental Figure S4 ACC: Schematic illustrations showing the distribution of neurons either dual stained for Rac1b+/p75NTR (red-brown) or singly for p75NTR (green) throughout the rostrocaudal extent of the NB in a representative severe AD case similar to Supplemental Figure S1CS3. Note the increase in double labeled Rac1b+/p75NTR neurons throughout the NB compared with NCI and MCI. Abbreviations: ac, anterior commissure; AMG, amygdala; Ch4al, cholinergic anterolateral NB portion; Ch4am, cholinergic anteromedial NB portion; Ch4id, cholinergic intermediate-dorsal NB portion; Ch4iv, cholinergic intermediate-ventral NB portion; Fx, fornix; GPe, external globus pallidus; GPi, internal globus pallidus; ic, internal capsule; oc, optic chiasm; Put, putamen nucleus. mmc4.pdf (282K) GUID:?7AA0B1D1-F5B9-4E97-BD1B-7EC0F8355FEF Supplemental Table S1 mmc5.xls (114K) GUID:?AA9C1740-99AC-41CF-8F44-BC9236398206 Abstract Cholinergic basal TAS 301 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 p75NTR 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 Rabbit polyclonal to OLFM2 impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75NTR and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75NTR-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75NTR-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/p75NTR-labeled NB neurons compared with Rac1b-negative/p75NTR-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. Rac1, a member of the Rho family of TAS 301 GTPases, is a ubiquitous intracellular transducer protein that interacts with specific effectors (eg, p-21-activated kinase) to mediate a diverse array of cellular functions, including cytoskeleton remodeling, microtubule stability, gene transcription, and superoxide production.1 Rac1 and related Rho GTPases regulate the formation, reorganization, and maturation of neuronal dendrites,2,3 indicating a key role for these proteins in modulating cellular processes underlying normative brain functions. Conversely, Rac1 dysfunction has been implicated in mental retardation syndromes3,4 and neurodegenerative diseases, including Parkinson’s disease5 and Alzheimer’s disease (AD).6 AD, the most common type of dementia in the elderly, is clinically characterized by a progressive cognitive.