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.

Figure 1. Aβ oligomers remove IRs from the neuronal surface membrane.

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.

Figure 2. A “cumulative hypothesis” for development of sporadic AD.

Listed are the different types of injuries that may impact the brain (yellow), peripheral organs (pink), or both systems (orange) throughout life and increase the risk of sporadic AD. The cross-talk between brain and peripheral tissues may eventually result in defective brain metabolic homeostasis, which might be closely linked to elevated Aβ production and progressive accumulation of AβOs in the brain. AD, which could thus be considered a form of dementia caused by metabolic dyshomeostasis, would manifest in the elderly as a result of the cumulative, lifelong impact in the peripheral tissues and the brain.

Figure 3. Boosting brain insulin signaling to combat AD.

(A) In healthy aging, IRs are present at synapses, and proper insulin signaling favors synapse function and leads to memory formation. (B) In early AD, accumulation of AβOs stimulates TNF-α signaling, which activates the JNK pathway (11, 54) and, possibly, PKR and IKK pathways. Activation of these stress-sensitive kinases, which can also be triggered by ER stress in peripheral tissues (69), results in IRS-1pSer, decreasing downstream insulin signaling (11, 31, 54). This contributes to initial cognitive impairment in early AD. (C) At later AD stages, increased accumulation of AβOs and their binding to synapses lead to removal of IRs from the neuronal plasma membrane (14, 15, 47). Additionally, TNF-α/JNK activation ultimately blocks insulin actions (11), contributing to severe impairment in cognition and memory. (D) Stimulation of insulin and GLP-1Rs blocks early AβO-induced defects in insulin signaling. Insulin protects neurons by preventing AβO binding to neurons (15). In addition, activation of GLP-1Rs by exendin-4 or liraglutide and of IRs by insulin prevents JNK activation, allowing physiological tyrosine phosphorylation of IRS-1 and stimulating downstream insulin signaling. (E) At later AD stages, activation of GLP-1Rs prevents inhibitory IRS-1pSer, stimulating insulin-related downstream signaling pathways and ameliorating cognitive and memory impairment. Red arrows indicate inhibitory pathways and green arrows indicate stimulatory pathways of insulin signaling.