LAUSR

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-β (Aβ) 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 Aβ 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.'