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

Abstract

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

Telomeric alterations in the default mode network during the progression of Alzheimer’s disease: Selective vulnerability of the precuneus

“…The present study indicates that telomere length alterations within hubs of the DMN are nuanced when examined in the context of AD neuropathology and cognitive performance. Future studies will evaluate telomere alterations using Q‐FISH, single‐cell and global gene expression profiling to identify the genetic signatures of cell populations that demonstrate telomere attrition in the DMN during the progression of AD 3,4 . The present findings indicate that telomeric homeostasis is affected in the PreC during the prodromal stage of AD.…”

“…TRF2 interacts with lamin A/C at the nuclear lamina, 91,92 suggesting that a molecular interaction between TRF2 and the nucleoskeleton affects genomic integrity, telomere stability and chromosome structure 92 . Perhaps telosome alterations affect the AD transcriptome via DDR activation by disrupting molecular interactions with TRF2, which could play a role in the selective vulnerability of the PreC to hypometabolism, 9,10,93 energy deficits 2,5 and dysregulation of gene transcription in MCI and AD 4 . Future qualitative and quantitative immunohistochemistry will be used to investigate cellular shelterin phenotypes, telomere functionality and their correlation with the findings observed in the current study.…”

“…The precuneus (PreC) corresponds to the mesial portion of Brodmann Area (BA) 7 and is a hub of the default mode network (DMN) that also includes frontal (BA10), inferior temporal (BA20) and posterior cingulate (BA23) cortices, which are compromised during the early stages of AD 1‐4 . PreC imaging studies show marked hypometabolism 5‐10 and extensive amyloid ligand binding in both mild cognitive impairment (MCI), a prodromal AD stage and frank AD 1,11,12 .…”

Targeting Calpain-2 for Alzheimer’s Disease Treatment

“…The pyramidal cells in layer III of the dlPFC have been an important focus of research, as these neurons are critical for higher cognitive functions 30,31 , and are selectively vulnerable to tau pathology and neurodegeneration in AD 32,33 , thus providing important clues about AD etiology. Studies of these neurons in rhesus monkeys have shown that they express the molecular machinery to magnify calcium signaling in dendritic spines at glutamate synapses (Fig.…”

Neuroinflammation in Alzheimer’s disease: microglial signature and their relevance to disease

“…Several studies have earlier examined the expression of neuroinflammatory genes in the prefrontal or entorhinal cortex of the patients with AD using single nucleus transcriptome analysis [ 18 – 20 ]. However, there are only a few transcriptomic studies focusing on the precuneus [ 21 , 22 ], the region of the brain, where Aβ accumulation is observed in preclinical AD patients [ 23 , 24 ]. Therefore, the transcriptomic analysis of precuneus is of particular interest, as it can provide novel insights into the response of microglia to Aβ in early AD.…”