Changes in the Extracellular Matrix with Aging: A Larger Role in Alzheimer's Disease
- Department of Neurosurgery, Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Review of Sano et al.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia (2023). Aging is a leading risk factor for sporadic onset of AD. During normal aging, regulatory signaling pathways that are critical for cellular health gradually become less effective, leading to impairment of physiological functions across all tissue systems (Zia et al., 2021). For example, in the healthy brain, the production and clearance of amyloid-β (Aβ) peptides are balanced to maintain appropriate levels of Aβ in the cells, vasculature, and extracellular space. However, with aging, the body loses the ability to maintain this process, leading to an increase of misfolded Aβ peptides and the generation of extracellular plaques (Hampel et al., 2021). These plaques are one of the characteristic pathological features of AD.
Insulin/insulin growth factor-1 (IGF-1) signaling, a major pathway implicated in the regulation of aging, may also play a pivotal role in Aβ pathogenesis (Sano et al., 2023). Insulin signaling begins when insulin secreted by the pancreas binds to an IGF-1 receptor, leading to phosphorylation of insulin receptor substrate proteins, IRS1-4 (Zia et al., 2021). These modified substrates independently control distinct intracellular cascades. Genetic deletion of one of these substrates, Irs2, in mice causes severe type 2 diabetes mellitus, with associated behavioral changes, impairments …
Correspondence should be addressed to Kathryn R. Jacobson at kathryn.jacobson{at}pennmedicine.upenn.edu or Hailong Song at hailong.song{at}pennmedicine.upenn.edu.
