Abstract
A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.
Highlights
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and a wide spectrum of complications including cardiovascular, ocular, renal, and immunological disturbances
Association (ADA), the term type 3 diabetes underlines the tight connection between these two apparently distinct diseases. Consistent with this view, more than 80% of patients suffering from Alzheimer’s disease (AD) develop diabetes or glucose intolerance [21], and postmortem analysis of brain from AD patients has detected a significant decreased expression and activation of IR, insulin-like growth factor 1 (IGF-1) and insulin receptor substrate-1 (IRS-1) [22], with a pattern resembling that observed during age-related changes [23]
Accumulation of Aβ in mitochondria causes mitochondrial swelling, reactive oxygen species (ROS) overproduction, impaired respiratory chain function [151,152] and altered calcium homeostasis [153,154], with subsequent further damage of mitochondrial structure, inhibition of ATP production, and defective energy metabolism. These findings suggest that Aβ aggregation in mitochondria precedes the subsequent, age-related, extracellular Aβ deposition responsible for synaptic damage in AD brains; according to this hypothesis, Aβ accumulation in mitochondria may represent the initial pathological event triggering mitochondrial perturbations, which in turn contribute to neurodegeneration [149]
Summary
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and a wide spectrum of complications including cardiovascular, ocular, renal, and immunological disturbances. Association (ADA), the term type 3 diabetes underlines the tight connection between these two apparently distinct diseases Consistent with this view, more than 80% of patients suffering from AD develop diabetes or glucose intolerance [21], and postmortem analysis of brain from AD patients has detected a significant decreased expression and activation of IR, insulin-like growth factor 1 (IGF-1) and insulin receptor substrate-1 (IRS-1) [22], with a pattern resembling that observed during age-related changes [23]. In T2DM patients, other AD-like brain changes linked with cognitive decline such as mitochondrial dysfunction [26,27], neuroinflammation, impaired learning and memory, and synaptic plasticity deficits [28] further support the presence of a causative link between diabetic and AD pathophysiology. During the progression of diabetes, any impairment in brain mitochondria electron chain may result in accumulation of fatty acid molecules and subsequent mitochondrial dysfunction.
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