Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimerʼs Disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain’s capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain’s propensity to accumulate aberrantly processed, mis-folded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle change...

Combination Treatment with a Novel Polyherbal Formulation and Metformin: A Single Blind Placebo-Controlled Study in Patients with T2DM and Cognitive Impairments

“…12,[30][31][32][33][34] The molecular and biochemical consequences of insulin resistance in the brain are caused due to impairments in the insulin signalling pathway that compromises neuronal survival, energy production, gene expression, plasticity and white matter integrity. 33,35,36 The brain undergoes a starvation state due to deficit in glucose uptake and utilization, thus causing oxidative stress, impairments in homeostasis and increased cell death. Impairments in insulin signalling results in neurodegeneration due to increased activity of kinases that aberrantly phosphorylates tau, generation of reactive oxygen species that damages proteins, nucleic acids and lipids, leads to accumulation of amyloid beta monomers and plaques, causes mitochondrial dysfunction and increase signalling through pro-inflammatory and pro-apoptosis cascades.…”

“…Impairments in insulin signalling results in neurodegeneration due to increased activity of kinases that aberrantly phosphorylates tau, generation of reactive oxygen species that damages proteins, nucleic acids and lipids, leads to accumulation of amyloid beta monomers and plaques, causes mitochondrial dysfunction and increase signalling through pro-inflammatory and pro-apoptosis cascades. [35][36][37][38] Also insulin resistance is associated with down-regulation of genes needed for cholinergic function, thereby further compromising neuronal plasticity, memory and cognition. 36,38 The basis of the neuroprotective effects of the test formulation is corroborated by several studies in animals and humans.…”

“…[35][36][37][38] Also insulin resistance is associated with down-regulation of genes needed for cholinergic function, thereby further compromising neuronal plasticity, memory and cognition. 36,38 The basis of the neuroprotective effects of the test formulation is corroborated by several studies in animals and humans. The polyherbal formulation is a combination of Bacopa monnieri, Hippophae rhamnoides and Dioscorea bulbifera.…”

Physical Activity, Weight Status, Diabetes and Dementia: A 34-Year Follow-Up of the Population Study of Women in Gothenburg

“…A perturbed insulin metabolism leading to insulin resistance both peripherally and in the brain has been proposed as an intermediate condition for both diabetes and dementia [27,28,29,30]. The observed interaction of obesity and low LTPA, both associated with e.g.…”

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

“…Many mechanisms have been suggested, such as insulin resistance and deficiency and impaired insulin receptor and insulin growth factor signalling, to result in advanced glycation end products that may induce cerebrovascular injury and vascular inflammation. 7,8 C-reactive protein (CRP) is an annular, pentameric protein found in blood plasma whose levels rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells.…”