Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) should be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions occurring in diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome. Although most of the diagnostic and therapeutic approaches over the past several decades have focused on amyloid-beta (Aβ42) and aberrantly phosphorylated tau, which could be caused by consequences of brain insulin resistance, the broader array of pathologies including white matter atrophy with loss of myelinated fibrils and leukoaraiosis, non-Aβ42 microvascular disease, dysregulated lipid metabolism, mitochondrial dysfunction, astrocytic gliosis, neuro-inflammation, and loss of synapses vis-à-vis growth of dystrophic neurites, is not readily accounted for by Aβ42 accumulations, but could be explained by dysregulated insulin/IGF-1 signaling with attendant impairments in signal transduction and gene expression. This review covers the diverse range of brain abnormalities in AD and discusses how insulins, incretins, and insulin sensitizers could be utilized to treat at different stages of neurodegeneration.

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…Studies in humans, both clinical and post‐mortem, as well as in animal models, suggest that some drugs, aimed at the treatment of MetS, could induce improvements in the cellular and behavioral functions present in AD (De la Monte, ).…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…Furthermore, numerous studies have identified a close correlation between insulin resistance and Aβ plaques [141]. Normally, the activation of the insulin pathway strengthens the degrading process of excessive Aβ and thus effectively avoids the formation of extracellular Aβ plaques.…”

Altered temporal lobe white matter lipid ion profiles in an experimental model of sporadic Alzheimer's disease

“…The characteristic neuropathological changes in AD include brain accumulations of hyper-phosphorylated tau (pTau)-containing cytoskeletal lesion, and increased amyloid-beta (Aβ42) deposits in plaques, vessels, and neurons (Kalaria and Ballard, 1999; Viola and Klein, 2015). However, other more extensive and universal pathologies, including atrophy of white matter (WM), loss of neurons and synaptic terminals, neuro-inflammation, reactive astrocytosis, micro-vascular disease, and increased cellular stress with activation of the unfolded protein response (de la Monte, 2016; Hyman et al, 2012; Montine et al, 2012; Nelson et al, 2012) have received relatively little attention. Failure to attend to the full spectrum of disease could account for the persistent difficulties in rendering accurate diagnoses and repeated failure of clinical trials designed to treat just one aspect of AD (de la Monte, 2016).…”

“…STZ model is that substantial evidence indicates that the major early abnormalities in AD include reductions in brain glucose metabolism, insulin/IGF trophic factor levels, and insulin/IGF-1 signaling through phosphoinositol-3-kinase (PI3K)-Akt pathways that regulate cell survival, energy metabolism, neuronal plasticity and WM integrity (de la Monte and Tong, 2014; de la Monte and Wands, 2008; Rivera et al, 2005; Steen et al, 2005; Talbot et al, 2012). Regarding WM, oligodendrocyte survival and function are regulated by insulin and insulin-like growth factor type 1 (IGF-1) signaling (Barres et al, 1993; Carson et al, 1993; Chesik et al, 2008) and brain diseases linked to insulin and IGF-1 trophic factor deficiencies or receptor resistances are associated with WM pathology (de la Monte, 2009, 2012, 2016; de la Monte et al, 2009). The i.c.…”