Progression of tau pathology in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Laurel Vana, Nicholas M. Kanaan, Isabella C. Ugwu, Joanne Wuu, Elliott J. Mufson, Lester I. Binder

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75 NTR, which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422+ neurons increased in number, p75 NTR+ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank NFT deposition.

Original languageEnglish (US)
Pages (from-to)2533-2550
Number of pages18
JournalAmerican Journal of Pathology
Issue number5
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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