Thursday, November 21, 2024
11/21/2024
Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia primarily attacking the aging population. Hippocampal synaptic injury and neurodegeneration are defining pathological features of the cognitive deficits in Alzheimer's disease (AD). In order to better understand the pathogenesis of the disease, and to improve AD treatment options, we need to elucidate the molecular mechanisms that cause cellular stress in the hippocampus. The growth hormone secretagogue receptor (GHSR), also known as ghrelin receptor, is highly expressed in neurons of the hypothalamus and hippocampus. In addition to its roles in stimulating appetite and growth hormone release, recent studies have revealed an important contribution of GHSR1a, the functional isoform of GHSR, in the regulation of hippocampal synaptic plasticity and memory consolidation. GHSR1a heteromerizes with the dopamine receptor D1 (DRD1), thus regulating DRD1-mediated modulation of synaptic plasticity. Moreover, recent studies have shown GHSR1a- dependent apoptosis of hippocampal neurons, indicating a critical role for GHSR1a in hippocampal neuronal survival. GHSR-null mice exhibit hippocampal pathology and cognitive impairments that resemble AD-like symptoms. In preliminary studies we found substantially reduced GHSR1a/DRD1 heteromerization in hippocampal tissue from human AD cases, as well as in an AD mouse model (5xFAD mice), even though the expression levels of membrane-bound GHSR1a and DRD1 remained relatively preserved. In addition, our preliminary studies revealed an unexpected physical interaction between GHSR1a and Amyloid beta (Aβ), a key mediator of AD, in both the AD patients and 5xFAD mice. Changes in GHSR1a/DRD1 heteromerization and the presence of GHSR1a/Aβ complexes were accompanied by increased apoptotic neuronal death. Finally, we found that GHSR1a deficiency exacerbates hippocampal pathology in the 5xFAD mice without significantly altering Aβ production. These observations lead us to hypothesize that GHSR1a dysfunction that results from its interaction with Aβ constitute a key molecular mechanism for hippocampal synaptic injury and neuronal death, leading to cognitive impairments in AD. Here, we will determine the influence of Aβ on GHSR1a function, and we will establish the link between GHSR1a deregulation and hippocampal synaptic injury, neuronal death, and cognitive deficits in 5xFAD mice. In addition, we will address the mechanisms underlying Aβ interaction-mediated GHSR1a dysfunction. Taken together, the proposed studies will allow the causative examination of the role of GHSR1a deregulation in hippocampal pathology in AD and the evaluation of GHSR1a as a therapeutic target for AD treatment. In addition, the results can be extended to further our understanding of hippocampal pathology in other neurodegenerative diseases that involve hippocampal amyloidopathy.
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