Neuroplasticity involves molecular changes in central nervous system (CNS) synaptic structure and function throughout life. The concept of neural organization allows for synaptic remodeling as a compensatory mechanism to the early pathobiology of Alzheimer’s disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (Aβ) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD.
The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). 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)/p75 NTR -mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. 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). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. 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. Findings 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. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75 NTR death receptor for the treatment of AD.
2019) Neuropathology and Applied Neurobiology 45, 380-397 HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease Aims: Alzheimer's disease (AD) is characterized by degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the major cholinergic input to the cortical mantle and is related to cognitive decline in patients with AD. Cortical histone deacetylase (HDAC) dysregulation has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in CBF degeneration during AD onset is unknown. We investigated global HDAC protein levels and nuclear HDAC2 immunoreactivity in tissue containing the nbM, changes and their association with neurofibrillary tangles (NFTs) during the progression of AD. Methods: We used semi-quantitative western blotting and immunohistochemistry to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD) or severe AD (sAD). Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei and their colocalization with the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3 and Thioflavin-S, a marker of b-pleated sheet structures in NFTs. Results: In AD patients, HDAC2 protein levels were dysregulated in the basal forebrain region containing cholinergic neurons of the nbM. HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. Conclusions: These findings suggest that HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction, NFT pathology, and cognitive decline during clinical progression of AD.
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