Unveiling Cholinergic Vulnerability During Aging and Chronic glial activation in Alzheimer's Disease Pathogenesis — The Association Specialists

Unveiling Cholinergic Vulnerability During Aging and Chronic glial activation in Alzheimer's Disease Pathogenesis (21469)

Erika Gyengesi 1 , Yossi Buskila 1 , Rose Chesworth 1 , Ingrid Wagnon 1 , Ilaria Rossetti 1 , Rashmi Gamage 1
  1. Western Sydney University, Penrith, NSW, Australia

Chronic neuroinflammation, a multifaceted response of the central nervous system (CNS) to various disruptive stimuli, encompasses reactions to infections, autoimmune insults, and protein misfolding, implicated in neurodegenerative disorders, notably Alzheimer's disease (AD). We hypothesize that chronic exposure to neuroinflammatory mediators exacerbates glial reactivity leading to cholinergic vulnerability during aging, and proposing a link between cholinergic transmission alterations and glial activation.

A comprehensive approach combining behavioral studies, in vitro electrophysiology assessing cholinergic neuron firing patterns, and immunohistochemistry combined with stereology and single-cell morphological analysis and qPCR was employed to investigate the excitability profile of single basal forebrain cholinergic neurons (BFCNs) in a transgenic mouse model of chronic neuroinflammation (GFAP-IL6).

Across age groups (4-, 12-, and 18-months), significant increases in microglial numbers within the medial septum were observed, accompanied by a notable decrease in cholinergic cell numbers at 12 and 24 months. Aging and chronic glial activation impacted septal cholinergic function, evident through alterations in passive and active membrane properties, firing patterns, and morphological changes. Cholinergic neuron reductions and increased astrocyte numbers during aging and chronic neuroinflammation, particularly evident in adult mice, were noted. The firing activity of cholinergic neurons was compromised, possibly due to altered membrane properties.

Neuroinflammation is a pivotal factor in neurodegenerative disorders, that involves astrocytes and microglia, and CNS homeostasis disruptions. Brain region-specific analyses revealed diverse responses to IL-6 overexpression, emphasizing the influence of age on neuroinflammatory impact and cholinergic vulnerability. These findings offer valuable insights into potential therapeutic strategies for mitigating neuroinflammatory-driven neurodegeneration, particularly in AD.

  1. Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum. Gamage R, Rossetti I, Niedermayer G, Münch G, Buskila Y, Gyengesi E. J Neuroinflammation. 2023 Oct 13;20(1):235. doi: 10.1186/s12974-023-02897-5.PMID: 37833764
  2. Chronic interleukin-6 mediated neuroinflammation decreases anxiety and impairs spatial memory in aged female mice. Wagnon IM, Niedermayer G, Muench G, Karl T, Chesworth R, Gyengesi E. Frontiers in Neuroscience. 2023. DOI: 10.3389/fnins.2023.1267818