Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease

Abstract

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

“…Decreased Slc18a3 signaling has deleterious effects on working memory and synaptic plasticity (104,105). Likewise, Ntf5 is up-regulated by MCS, whereas decreases in the human homolog, Ntf4, have been previously shown by our group within CA1 pyramidal neurons in mild cognitive impairment and AD (106). Further, in Ntf4 and Ntf5 knockout mice, traumatic brain injury causes increased cell death, and reversal of Ntf4 and Ntf5 deficiency reduces cell loss (107).…”

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

“…Approximately 576 cDNAs of interest to neurobiology and neurodegeneration were utilized on the array platform (Ginsberg et al, 2017; Tiernan et al, 2016b). Hybridization signal intensity was determined using Image Quant software (GE Healthcare) and quantified by subtracting background using an empty vector (pBluescript).…”

Maternal Choline Supplementation Alters Basal Forebrain Cholinergic Neuron Gene Expression in the Ts65Dn Mouse Model of Down Syndrome

“…Since the MS/VDB region contains a heterogeneous population of neurons, analyses based on whole region homogenates are ill‐suited for BFCN‐specific profile analysis (Mesulam et al , ; Rye et al , ; Ginsberg et al , ; ). LCM provides a rigorous and reproducible method to isolate single cells based on a specific cellular phenotype (Ginsberg et al , ; ; ) and can be combined with custom‐designed microarrays containing probes relevant to BFCNs, DS, cognitive dysfunction, and AD that hybridize the cDNA made from LCM BFCN mRNA isolates (Ginsberg and Che, ). This approach is highly effective for comparative group analysis and provides valuable insight into the molecular pathophysiology of DS, AD, and MCS treatment.…”