1/8/2024 0 Comments El yate fajardoFindings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). We demonstrate and validate an interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit.Ĭonclusions: We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamate, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. Results: Ts65Dn mice had unique MSN BFCNs transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Methods: We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. Background: Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer’s disease (AD).
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