Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 9, 204

Aberrant Insulin Signaling in Alzheimer's Disease: Current Knowledge


Aberrant Insulin Signaling in Alzheimer's Disease: Current Knowledge

Gaurav Bedse et al. Front Neurosci.


Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.

Keywords: Alzheimer's disease; beta amyloid; insulin signaling; insulin-like growth factor; phosphorylated tau.


Figure 1
Figure 1
Aberrant brain insulin signaling in Alzheimer's Disease (AD). Schematic outline of neuronal insulin signaling in the normal brain (A) and AD brain (B). Under physiological conditions, insulin binding to its receptor triggers phosphorylation of insulin receptor substrate-1 (IRS-1). This results in phosphoinositide 3-kinase (PI3K) activation and downstream cellular responses that facilitate neuronal growth, neuronal survival, synaptic plasticity, learning and memory, etc. Activation of the IR can result in both vasodilatation and vasoconstriction and under physiological conditions there is a balance of both processes to regulate the immediate metabolic requirements of various tissues. In AD, accumulation of amyloid-β (Aβ) oligomers leads to increased tumor necrosis factor-alpha (TNF-α) levels and activation of stress kinases such as c-Jun N-terminal kinase (JNK) resulting in inhibitory serine phosphorylation of IRS-1 (1). Aβ oligomers cause removal of IRs from the cell surface mediated by Casein Kinase 2 (CK2) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII) and redistribute them to cell bodies (2). Insulin resistance lowers the expression of Aβ-degrading insulin degrading enzyme (IDE) (3). Lowered IDE expression further decreases the availability of IDE for Aβ degradation. The reduction in brain insulin signaling increases GSK-3β activity (4), which increases abnormal tau phosphorylation. Deficient insulin signaling leads to impairment in nerve growth, synaptic plasticity, learning and memory, etc. (5). Aberrant phosphorylation of IRS causes an imbalance in homeostatic regulation of vascular function (6). This decreased production of NO may results in decreased cerebral blood flow and increased pro-inflammatory cytokines and reactive oxygen species production.

Similar articles

See all similar articles

Cited by 65 articles

See all "Cited by" articles


    1. Ashpole N. M., Sanders J. E., Hodges E. L., Yan H., Sonntag W. E. (2015). Growth hormone, insulin-like growth factor-1 and the aging brain. Exp. Gerontol. 68, 76–81. 10.1016/j.exger.2014.10.002 - DOI - PMC - PubMed
    1. Aulston B. D., Odero G. L., Aboud Z., Glazner G. W. (2013). Alzheimer's Disease and Diabetes, in Understanding Alzheimer's Disease, ed Zerr I., editor. (InTech), Available online at:
    1. Authier F., Posner B. I., Bergeron J. J. (1996). Insulin-degrading enzyme. Clin. Invest. Med. 19, 149–160. - PubMed
    1. Baker L. D., Cross D. J., Minoshima S., Belongia D., Watson G. S., Craft S. (2011). Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68, 51–57. 10.1001/archneurol.2010.225 - DOI - PMC - PubMed
    1. Banks W. A., Owen J. B., Erickson M. A. (2012). Insulin in the brain: there and back again. Pharmacol. Ther. 136, 82–93. 10.1016/j.pharmthera.2012.07.006 - DOI - PMC - PubMed

LinkOut - more resources