Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis

NEUROPHARMACOLOGY

卷:136

Review

Bloom, George S.^1,2,3  Lazo, John S.^4,5  Norambuena, Andres¹ 

[1] Univ Virginia, Dept Biol, POB 400328, Charlottesville, VA 22904 USA

[2] Univ Virginia, Dept Cell Biol, Charlottesville, VA USA

[3] Univ Virginia, Dept Neurosci, Charlottesville, VA USA

[4] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

[5] Univ Virginia, Dept Chem, Charlottesville, VA USA

关键词: Alzheimer's disease;    Insulin;    Amyloid-beta;    Tau;    mTOR;   

DOI  :  10.1016/j.neuropharm.2017.09.016

来源: Elsevier

【 摘 要 】

The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD? The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive. Here we review recent findings that mechanistically link soluble forms of amyloid-beta (A beta) and tau, the respective building blocks of the amyloid plaques and neurofibrillary tangles that accumulate in the brains of AD patients, with neuronal decline that is associated with poor insulin responsiveness and may begin long before AD symptoms become evident. We discuss how A beta and tau work coordinately to deprive neurons of functionally accessible insulin receptors and dysregulate normal signaling by the protein kinase, mTOR. Finally, we suggest how newly gained knowledge about pathogenic signaling caused by reduced brain insulin signaling might be exploited for improved early detection and therapeutic intervention for AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free