Defining the molecular pathological events underlying the selective vulnerability of neuron populationsassociated with cognitive decline during the progression of Alzheimer's disease (AD) is crucial for biomarkerdevelopment and therapeutics to slow/prevent the onset of this disease. Project 4 of this Program Projectprovided novel insights into the neurotrophic mechanisms underlying the survival of the cholinergic basalforebrain (CBF) neurons, which provide the cholinergic innervation the entire cortical mantle andhippocamppus, play a key role in memory and attention, their degeneration is associated with clinicalseverity and disease duration as well as targets of drug therapies during the onsest of AD. This area gainedgreater importance following a recent Phase 1 clinical trial demonstrating that ex vivo NGF (CBF neuronsurvival factor) gene therapy improves cognition and induces CBF neuronal sprouting in mild AD. Ourstriking findings showing a shift in the balance between cell survival and cell death mechanisms, aphenotypic reduction in trkA and p75NTR but not ChAT containing CBF neurons as well as a shift in the ratioof 3Rtau/4Rtau within CBF neurons in people with mild cogntivie impairment suggest that subtle alterationsin the balance of cellular molecules underlie CBF neuron death. The pro-apoptotic effect(s) of p75NTRmediatedproNGF signaling is, in part, dependent on its interactions with the chaperone neurotensinreceptor, sortilin, which we have shown to increase in the AD cortex (see Preliminary data) suggest a role inCBF cell death in AD. Project Specific Aims will test the following hypothesis: 1 A. that cortical sortilin level isincreased in the MCI and AD compared to NCI cortex. 1B. that TrkA is increased while p75NTR, sortilin andproNGF protein levels remain stable in hippocampus in MCI (see Preliminary data). 2A. that there aregreater numbers of ChAT only immunopositive nucleus basalis neurons compared of co-labeled for ChATand NGF receptors. 2B. that classes of genes for cell survival signaling, regulation of transcription, andcholinergic neurotransmission are differentially altered in ChAT only compared to those co-labeled also forChAT and TrkA or p75NTR during the progression of AD. 3. that alteration in the expression ratio of3Rtau/4Rtau isoforms is an early marker in the evolution of CBF NFTs during the progression of AD. Thesefindings will directly translate to the development of new drugs for CBF cell survival in MCI and AD.
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