Alzheimer’s disease and insulin resistance: translating basic science into clinical applications
Fernanda G. De Felice
Fernanda G. De Felice
Published February 1, 2013
Citation Information: J Clin Invest. 2013;123(2):531-539. https://doi.org/10.1172/JCI64595.
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Science in Medicine

Alzheimer’s disease and insulin resistance: translating basic science into clinical applications

Abstract

Alzheimer’s disease (AD) and diabetes are currently considered among the top threats to human health worldwide. Intriguingly, a connection between these diseases has been established during the past decade, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. In this article, the molecular and cellular mechanisms underlying defective brain insulin signaling in AD are discussed, with emphasis on evidence that Alzheimer’s and diabetes share common inflammatory signaling pathways. I put forward here a hypothesis on how a cross-talk between peripheral tissues and the brain might influence the development of AD, and highlight important unanswered questions in the field. Furthermore, I discuss a rational basis for the use of antidiabetic agents as novel and potentially effective therapeutics in AD.

Authors

Fernanda G. De Felice

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Figure 1

Aβ oligomers remove IRs from the neuronal surface membrane.

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Aβ oligomers remove IRs from the neuronal surface membrane. A composite ...
A composite picture created by merging immunofluorescence images of a control neuron (left image) and a neuron exposed to Aβ oligomers (AβO) (right image). Left image: A healthy neuron devoid of AβOs (no red puncta observed) presents abundant dendritic IRs (green puncta). A schematic of a dendrite segment is represented in the left circle. Physiological levels of Aβ are produced and there is no accumulation of AβOs. The presence of IRs at the surface membrane allows proper insulin signaling and synapse function. Right image: AβO binding to neurons (red puncta) causes loss of surface IRs (IR; green puncta), leading to IR internalization (14, 15, 47). A schematic of a dendrite segment is represented in the right circle: AβOs accumulate as a result of elevated Aβ levels generated by cleavage of APP by the β-secretase (also known as BACE, β-amyloid precursor cleaving enzyme) and subsequent cleavage by γ-secretase (a complex consisting of at least 4 components: nicastrin, APH-1, PEN-2, and presenilin). AβOs attach to a putative receptor complex (not shown; ref. 45) at the neuronal plasma membrane, causing removal of IRs from the membrane and disrupting insulin signaling and synapse function.