Aberrant insulin signaling in Alzheimer's disease: current knowledge

Abstract

Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.

The Diabetic Brain and Dementia

“…Although insulin mitigates Aβ deposition and hyperphosphorylation of tau [17,31], DM in combination with ApoE ε4 may lead to excessive phosphorylation of tau [32], but only in subjects with late stage AD [21]. DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms [31].…”

“…DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM [14]. However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed [3,4,[15][16][17][18][19][20].…”

“…DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM [14]. However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed [3,4,[15][16][17][18][19][20].Autopsy studies stated that diabetic patients show significantly less AD pathology (senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, etc.) but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM [5,[21][22][23][24][25][26][27].…”

The diabetic brain and cognition

“…Moreover, DM facilitates cognitive decline in patients with mild AD compared to those without comorbid DM (Jellinger 2015a;Ascher-Svanum et al 2015). However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed (Feinkohl et al 2015;Abner et al 2016;Hao et al 2015;Chiu et al 2015;Verdile et al 2015;Bedse et al 2015;De Felice et al 2014), including vascular brain disease, insulin resistance, and other metabolic effects on the brain.…”

The Effect of Apocynin on Motor and Cognitive Functions in Experimental Alzheimer’s disease

“…TNF-a levels are increased in AD brain and cerebrospinal fluid. Impaired neuronal insulin signaling in AD is connected to that soluble proteins of the amyloid-b (Ab) peptide-synaptotoxins accumulate in AD and cause insulin receptor substrate-1 inhibition through TNF-a activation (9,10).…”