The global rise in obesity and type 2 diabetes (T2D) has led to an increased focus on understanding the relationship between metabolic disorders and neurodegenerative diseases such as Alzheimer's disease (AD). The term Type 3 diabetes has been proposed to describe AD, given the significant overlap in risk, comorbidity, and pathophysiological pathways between T2D and AD. This overlap is particularly evident in the context of insulin resistance, a key feature of metabolic disorders, which has been identified as a significant risk factor for neurodegeneration and cognitive impairment.
Insulin resistance is a state in which cells fail to respond adequately to insulin, leading to impaired glucose uptake and utilization. This can result in hyperglycemia, inflammation, and oxidative stress, all of which can contribute to neuronal damage and cognitive decline. In the brain, insulin resistance can lead to impaired synaptic plasticity, reduced neuronal survival, and increased neuroinflammation, all of which are hallmarks of AD.
Obesity, a major risk factor for insulin resistance and T2D, has also been linked to an increased risk of AD. Obesity-induced inflammation and oxidative stress can exacerbate insulin resistance and contribute to neuronal damage. Moreover, obesity can lead to dyslipidemia, characterized by high levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol, which has been associated with increased Aβ levels in the brain, a key pathological feature of AD.
Interestingly, recent research has highlighted the role of nuclear hormone receptors (NHRs) in the regulation of metabolism and inflammation, and their potential as therapeutic targets for metabolic disorders and AD. One such NHR is NHR-49, a homolog of mammalian hepatocyte nuclear factor 4 α and peroxisome proliferator-activated receptor α. NHR-49 has been shown to regulate lipid metabolism, stress adaptation, innate immune responses, and aging in Caenorhabditis elegans, a model organism for studying aging and neurodegeneration.
Another key player in the interplay between metabolic disorders and AD is myostatin (MSTN), a protein that regulates muscle growth. MSTN has been implicated in the regulation of insulin sensitivity and glucose metabolism, and alterations in MSTN signaling have been associated with obesity, insulin resistance, and T2D. Interestingly, MSTN has also been linked to neurodegeneration, with studies showing that MSTN can induce neuroinflammation and contribute to neuronal damage.
In the context of AD, MSTN has been shown to regulate amyloid-β (Aβ) production and tau phosphorylation, two key pathological features of AD. Moreover, MSTN can induce neuroinflammation by activating microglia, the resident immune cells of the brain, and promoting the production of pro-inflammatory cytokines. This suggests that targeting MSTN could be a potential therapeutic strategy for AD.
