Expression profiling of precuneus layer III cathepsin D‐immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability

摘要: The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau-containing neurofibrillary tangle (NFT) pathology during onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), marker vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom-designed microarray profiling determine genetic signature CatD-positive-layer accrued from postmortem tissue obtained Rush Religious Orders Study (RROS) cases premortem clinical diagnosis no cognitive impairment (NCI), mild (MCI) AD. Expression revealed significant differential expression transcripts in MCI AD compared NCI that underlie signaling defects, including dysregulation genes endosomal-lysosomal autophagy pathways, cytoskeletal elements, AD-related genes, ionotropic metabotropic glutamate receptors, cholinergic enzymes markers monoamine neurotransmission as well steroid-related transcripts. Pervasive defects both were found select these gene ontology categories, underscoring vulnerability corticocortical progression dementia. Select dysregulated detected via analysis validated using qPCR. In summary, CatD -positive mosaic not previously appreciated terms their indication systems-wide DMN.