Aberrant insulin signaling in Alzheimer's disease: current knowledge.

Gaurav Bedse,Tommaso Cassano,Gaetano Serviddio,Fabio Di Domenico

doi:10.3389/fnins.2015.00204

Gaurav Bedse, Tommaso Cassano + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2015.00204

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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.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia
This review focuses on the recent progress in our understanding of the neuronal insulin signaling in the pathogenesis and progression of AD
- Strong insulin immunoreactivity in pyramidal neurons compared to age-matched controls - Unchanged insulin and c-peptide levels - Increased insulin receptor (IR) density - No significant difference in insulin-like growth factor (IGF)-1binding

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia. About 35.6 million people worldwide are suffering from AD, and disease prevalence is expected to affect 115 million by 2050 (Wortmann, 2012). The insulin/insulin-like growth factor (IGF) signaling is important for neuronal growth, synaptic maintenance and neuroprotection (Stockhorst et al, 2004; Van Dam and Aleman, 2004). Ample number of evidence suggested that alterations in brain insulin metabolism could be one pathological factor for neurodegenerative diseases including AD. In support of this hypothesis, AD patients have shown reduced brain insulin receptor sensitivity, hyperphosphorylation of insulin receptor and downstream second messenger such as insulin receptor substrate-1 (IRS-1) and attenuated insulin and insulin-like growth factor receptor expression (Watson and Craft, 2003; Rivera et al, 2005; Steen et al, 2005; Holscher and Li, 2010; Talbot et al, 2012; de La Monte, 2012c; Freiherr et al, 2013).

Conclusions

Findings

IU for 6 days