Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

Abstract

Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Reduces Alzheimer Disease-Associated Tau Hyperphosphorylation in the Hippocampus of Rats with Type 2 Diabetes

“…41 It has been identified that impaired insulin signaling pathway in the brain might be an important reason to the hyperphosphorylation of tau protein, restoring brain insulin signaling pathway is potentially a novel strategy for treating AD. 42 Catalyzed by the high importance of the brain insulin 37 and the failure of brain insulin therapy for its unexpected and inconvenient, the scientific interest in other factors acting via brain insulin signaling pathway and its downstream AD-associated hyperphosphorylated tau protein began to increase. In this present study, we found that intraperitoneal injection of EX-4, a highly selective GLP-1 receptor agonist, which has been approved for treating T2D, increased insulin signaling pathway in the brain, leading to inhibition of GSK-3β and reversed hyperphosphorylation of tau protein in a rat model of T2D.…”

Brain metabolic dysfunction at the core of Alzheimer's disease

“…The basic concept is that cytotoxic ceramides generated in liver and probably also visceral fat, leak into peripheral blood following injury or cell death caused by local tissue inflammation. Cytotoxic ceramides then traffic through the circulation, and due to their lipid soluble nature, cross the blood–brain barrier and exert neurotoxic and neurodegenerative effects by impairing insulin signaling [7,144,207] and activating pro-inflammatory cytokines [67,208]. This scheme explains how brain insulin resistance, which is an early and important feature of AD, could be mediated by peripheral insulin resistance diseases that are associated with hepatic or visceral fat accumulation, inflammation, dysregulated lipid metabolism, ER/oxidative stress, mitochondrial dysfunction, and activation of pro-death signaling networks [142,144,207].…”

Plasma leptin levels and free leptin index in women with Alzheimer's disease

“…It is the most common form of dementia. Due to the progress in medicine resulting in extended life-span, the number of patients with sporadic form of AD is growing rapidly (de la Monte, 2012). Hence, it is a crucial healthcare problem to assess all risk factors and, consequently, to find proper and effective therapies of pre-AD dementia stages.…”