Insulin resistance and Alzheimer's disease - PubMed (original) (raw)

Review

Insulin resistance and Alzheimer's disease

Suzanne M de la Monte. BMB Rep. 2009.

Abstract

Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

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Fig. 1

Fig. 1

Dual and overlapping pathways of insulin/IGF resistance mediated neurodegeneration. CNS neuronal survival, metabolic activity, and homeostasis are stimulated by insulin and IGF-1, which promote neurotrophin expression and plasticity for maintenance of normal brain structure, learning, and memory. Peripheral insulin resistance diseases such as T2DM and NASH, contribute to neurodegeneration through increased production of cytotoxic ceramides and other toxic lipids, which cause insulin resistance, mild cognitive impairment (MCI), and limited neurodegeneration. Environmental exposures, including nitrosamines, plus genetic factors, cause insulin and IGF resistance, which leads to neurodegeneration. T2DM and other peripheral insulin resistance diseases exacerbate the neurodegeneration cascade due to increased production of toxic lipids and ceramides. Finally, oxidative stress and cytokine activation contribute to neurodegeneration and dementia, but alone are not sufficient to cause dementia.

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