Department of Medicine and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
Address correspondence to: Warren J. Strittmatter, Duke University Medical Center, Bryan Research Bldg., Room 227, Durham, North Carolina 27710, USA. Phone: 919.684.6274; Fax: 919.684.6514; E-mail: firstname.lastname@example.org.
First published March 22, 2012 - More info
Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira, Fernanda G. De Felice
While a potential causal factor in Alzheimer’s disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and IRS-1 pS636/639. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino, Krista R. Kawaguchi, Andrew J. Samoyedny, Robert S. Wilson, Zoe Arvanitakis, Julie A. Schneider, Bryan A. Wolf, David A. Bennett, John Q. Trojanowski, Steven E. Arnold
Clinical vignette: A 59-year-old aeronautical engineer is referred to you for evaluation because of increasing difficulty with job performance over the last several years. Difficulty managing home finances, getting lost driving, and forgetting appointments have become common. Previously outgoing, he is now depressed and irritable. After appropriate neurologic assessment, including brain imaging and metabolic studies, you make the diagnosis of Alzheimer’s dementia and are asked by the patient’s family what treatment is available.
Although the disease was first described clinically and pathologically in 1907, clinical care in 2012 is sadly limited to medications that only treat symptoms. Two classes of drugs are FDA approved: acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and an NMDA receptor antagonist (memantine). Both classes typically produce only minimal and transient symptomatic improvement in memory and well-being. Antidepressant and antipsychotic drugs are sometimes helpful, but several carry black box warnings for use in patients with dementia.
In his seminal manuscript, Alzheimer described two microscopic lesions, the extracellular neuritic plaque and the intracellular neurofibrillary tangle (1). The neuritic plaque is formed by β-sheet aggregation of the amyloid-β (Aβ) peptide. Aβ peptide is generated by the proteolytic cleavage of transmembrane amyloid precursor protein (APP) by two proteases, β- and γ-secretase (2). Initial hypotheses of Alzheimer’s disease (AD) pathogenesis proposed a central role of the amyloid neuritic plaque in producing dementia. More recent observations, however, demonstrate that small, soluble Aβ oligomers (prior to their self-assembly into the neuritic plaque) directly injure neurons. Unfortunately, small-molecule inhibitors of β- and γ-secretase have failed to demonstrate clinical benefit in randomized clinical trials (3). These recent failures have led to a reappraisal of the strategies in AD drug development (3) and the need to identify additional molecular pathways in AD pathogenesis that might yield better therapeutic targets.
In this issue of the JCI, two studies make great strides in revealing a molecular pathway in AD that can be modified by drugs already approved by the FDA for other indications (4, 5). Previous studies have suggested that the molecular pathophysiology of AD significantly overlaps with that of type 2 diabetes and the metabolic syndrome, most notably in insulin resistance. Talbot et al. now demonstrate that insulin resistance in AD occurs not only in peripheral tissues, but also in the brain (4). The authors show that hippocampal brain slices in AD were less responsive to insulin than controls because of increased phosphorylation of IRS-1 that attenuated downstream Akt and ERK signaling. Brain insulin resistance in AD was not dependent on diabetes, or on the APOE4 genotype, which also affects the Akt pathway (6) and is a major determinant of risk for non-Mendelian AD.
Demonstrating insulin resistance in the AD brain has therapeutic implications, since this pathway can be modified by FDA-approved insulin-sensitizing drugs: metformin, the glucagon-like peptide–1 (GLP-1) mimetics exenatide and liraglutide, and PPARγ agonists. Also in this issue, Bomfim et al. demonstrate a critical role of the soluble Aβ oligomer in producing brain insulin resistance in AD and successfully demonstrate pharmacologic manipulation of this pathway by a GLP-1 agonist (5). Using multiple model systems, the authors show that soluble Aβ oligomers increased the production of the inflammatory cytokine TNF-α, leading to phosphorylation of IRS-1 by JNK. Moreover, a small-molecule activator of the GLP-1 receptor, developed to treat type 2 diabetes, reduced the phosphorylation of IRS-1 in the brain and improved cognition in a mouse model of AD.
Additional support for the pharmacologic enhancement of insulin signaling to treat AD comes from other investigators who have shown that nasally inhaled insulin improved clinical outcomes in small trials (7).
Dementia is defined as a gradual decline of cognitive skills sufficiently severe that the patient has difficulty with activities of daily living. Patients and families are typically overwhelmed when the diagnosis is first mentioned. While I prescribe the FDA-approved drugs mentioned above, it is important to emphasize the critical role played by advocacy groups, such as the Alzheimer’s Association, social workers, and multidisciplinary clinics, in the care of these patients. Structured education helps inform the family about the increasing needs for safety supervision, daily care, and establishing legal guardianship for financial and health decisions. The studies highlighted above suggest a path forward in the development of new therapies for AD by targeting the IRS-1/Akt pathway and may soon provide hope to patients with this devastating disease.
Conflict of interest: The author has declared that no conflict of interest exists.
Reference information: J Clin Invest. 2012;122(4):1191. doi:10.1172/JCI62745.
See the related articles at Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline and An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease– associated Aβ oligomers.