COMMENTARY

Linking type 2 diabetes and Alzheimers disease

Weiping Hana,b,1 and Cai Lic,1
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science Technology and Research, Singapore 138667; bDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; and cMerck Research Laboratories, Rahway, NJ 07065
a

ince the initial Rotterdam study suggesting an increased risk to develop dementia and Alzheimers disease (AD) in patients with type 2 diabetes mellitus (T2D), a number of clinical and epidemiological studies have provided further direct evidence to strengthen the link between T2D and AD (1, 2). The possibility that T2D patients might be at increased risk in developing AD has serious societal implications. It is estimated that 5.3 million people in the United States and more than 30 million worldwide are living with AD, and the number is destined to increase dramatically over the next two decades as the population ages. The direct and indirect cost associated with AD in the United States alone has reached 172 billion US dollars annually (3). The situation for T2D is hardly reassuring: There are more than 23 million T2D patients in the United States alone, and 18 million of those might have as much as 50% higher risk than a nondiabetic to develop AD. T2D often leads to cardiovascular complications and other conditions that kill the patients before AD typically strikes, usually when the patients are in their 70s. However, as the therapeutic treatment advances for diabetes in the near future, T2D patients will most likely live longer, and the world may soon be facing the daunting challenge of dealing with a new population of AD sufferers with T2D and, possibly, other metabolic complications. Over the last decade, researchers have been busy investigating the biological basis underlying the link between T2D and AD. In PNAS, the study by Takeda et al. (4) provides further understanding of potential underlying mechanisms that link AD and T2D by establishing two new mouse models and studying these mice by using a wide range of well-dened techniques. The pathogenesis of AD begins with impaired synaptic function, which may result from the accumulation of amyloid- (A) peptide (58). For many years, researchers have focused on the insoluble deposits of amyloid brils as the leading cause of memory loss and as the culprit of AD. More recent ndings, however, suggest soluble A oligomers may be the cause of memory loss, especially in the early stages of AD, because A oligomers inhibit long-term potentiation in neurons, a well-adopted experimental paradigm for learning and memory (6, 9). A is
www.pnas.org/cgi/doi/10.1073/pnas.1002555107

Fig. 1. The underlying links between AD and T2D. (A) Insulin resistance as a mechanistic link between AD and T2D. Insulin resistance in peripheral tissues and organs, when coupled with relative insulin deciency, causes T2D. On the other hand, central insulin resistance, together with reduced brain insulin levels that might have resulted from T2D, leads to accumulation of -amyloid and, consequently, AD. (B) Inammation as a mechanistic link between AD and T2D. Through its inuence on islet function and peripheral insulin sensitivity, inammation accelerates the development of T2D. Cerebrovascular and central inammation, along with increased accumulation of -amyloid, disrupts normal synaptic function, a starting point of AD pathological progression.

produced from amyloid precursor protein (APP) by serial proteolytic reactions catalyzed by -site of APP cleaving enzyme (BACE) and a multiprotein complex -secretase, in which presenilin is likely the catalytic component (10). T2D is caused by relative insulin deciency, which may be the result of insufcient insulin supply due to defective insulin secretion and/or reduced insulinsecreting -cell mass, and/or impaired insulin sensitivity in peripheral metabolic organs, such as liver and muscle. Obesity is believed to be caused by impaired central

response to adipose tissue-derived hormone leptin, whose major function is to reduce food intake and to promote energy expenditure (11). Insulin and leptin exert their effects through complex signaling cascades and share some common components in the two pathways. Because obesity often fuels the development of T2D, T2D and obesity are sometimes collectively referred to as diabesity. In addition to their peripheral functions in the regulation and maintenance of physiological homeostasis, insulin and leptin also have profound effects on brain functions. Indeed, both have been shown to regulate neuronal and synaptic functions within hippocampus, cortex, and cerebellum, to protect neurons against neurodegeneration and cell death, and to affect cognition and behavior (1215). Furthermore, insulin and leptin also regulate A levels by modulating A production via their actions on BACE and/or -secretase, as well as by modulating A degradation via A-degrading enzymes, such as insulin-degrading enzyme (1619). It is conceivable that insulin actions or their lack may be a link between T2D and AD. Some have gone so far as to refer to AD as type 3 diabetes to emphasize the potential endocrine links between these diseases (20). Takeda et al. (4) explore insulin action and insulin resistance in the development of cognitive impairment by crossing the ob/ob or NSY (NagoyaShibata-Yasuda) mouse, two wellestablished T2D mouse models, into the APP23 transgenic mouse background, a well-studied AD mouse model. The ob/ob mouse is leptin decient, whereas the NSY mouse is an inbred strain with spontaneous diabetes that resembles human T2D. In contrast to the ob/ob mice, the NSY mice do not develop severe obesity, allowing the study of T2D in the absence of obesity (21). The APP23 mouse line, generated by overexpressing APP751 harboring the Swedish double mutation (K670N and M671L) under the murine Thy1 promoter, has an 7-fold overexpression of the mutant APP above

Author contributions: W.H. and C.L. wrote the paper. The authors declare no conict of interest. See companion article on page 7036.
1

To whom correspondence may be addressed. E-mail: cai_li@ merck.com or weiping_han@sbic.a-star.edu.sg.

PNAS | April 13, 2010 | vol. 107 | no. 15 | 65576558

endogenous APP (22). These mice show A deposits at 6 months of age, and the deposits increase in size and number with age and eventually occupy a substantial area of the neocortex and hippocampus in 24-month-old mice. Takeda et al. (4) performed metabolic and behavioral tests on the two new mouse lines, APP+-ob/ob and APP+-NSY. They nd that in both lines, diabetes exacerbated cognitive dysfunction without a signicant increase in A levels. Furthermore, they nd that brain insulin levels were reduced, and Akt phosphorylation, a key step in insulin signaling, was severely impaired. These ndings provide experimental evidence to support the notion that impairment of insulin signaling might be a mechanistic link underlying T2D and AD: Peripheral impairment causes T2D and central impairment leads to AD (Fig. 1A). In addition to impaired insulin signaling, Takeda et al. (4) nd that diabetes accelerated the appearance of cerebrovascular inammation and A deposition, as evidenced by increased levels of proinammatory cytokines IL-6 and TNF, as well as dense amyloid deposits in blood vessels. In recent years, inammatory pathways, including that of NFB, have been linked to metabolic syndrome and neurodegenerative diseases, including AD. As inammation is often not restricted to central or peripheral tissues or organs, it is tempting to hypothesize that inammation may be another mech1. Ott A, et al. (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53:1937 1942. 2. Kroner Z (2009) The relationship between Alzheimers disease and diabetes: Type 3 diabetes? Altern Med Rev 14:373379. 3. Alzheimers Association (2010) 2010 Alzheimers Disease Facts and Figures (Alzheimers Association, Chicago, IL). 4. Takeda S, et al. (2010) Diabetes accelerated memory dysfunction via cerebrovascular inammation and A deposition in Alzheimer mouse model with diabetes. Proc Natl Acad Sci USA 107:70367041. 5. Selkoe DJ (2002) Alzheimers disease is a synaptic failure. Science 298:789791. 6. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimers disease. Neuron 44:181193. 7. Zhang C, et al. (2009) Presenilins are essential for regulating neurotransmitter release. Nature 460:632636. 8. Klein WL (2006) Synaptic targeting by A beta oligomers (ADDLS) as a basis for memory loss in early Alzheimers disease. Alzheimers Dement 2:4355.

anistic link underlying T2D and AD (Fig. 1B). Interestingly, in these new mouse lines, the relationship did not end with just T2Ds effects on AD; Takeda et al. (4) were able to show that AD could also accelerate the development of diabetic phenotype.

AD and T2D may share common cellular and molecular mechanisms.

The reciprocal actions between AD and T2D thus form a vicious cycle, further illustrating the possibility that AD and T2D may share common cellular and molecular mechanisms. Although the study by Takeda et al. (4) provides signicant insights and experimental evidence on the mechanistic link between AD and T2D, there remain some important questions to be addressed. First, although APP+-ob/ob mice demonstrated more severe cognitive decit than APP23 mice, both APP23 and APP+-ob/ob mice also exhibited signicant and comparable reductions in insulin levels, thus insulin and insulin action alone could not fully account for the observed difference in cognition. Considering the importance of leptin signaling on brain functions, it is conceivable that leptin may also be in9. Walsh DM, et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535539. 10. Shah S, et al. (2005) Nicastrin functions as a gammasecretase-substrate receptor. Cell 122:435447. 11. Zhang Y, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425432. 12. Harvey J (2007) Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol 7: 643647. 13. Morrison CD (2009) Leptin signaling in brain: A link between nutrition and cognition? Biochim Biophys Acta 1792:401408. 14. Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177:125134. 15. Chiu SL, Chen CM, Cline HT (2008) Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58:708719. 16. Eckman EA, Eckman CB (2005) Abeta-degrading enzymes: Modulators of Alzheimers disease pathogene-

volved. Future studies investigating defective leptin signaling in the absence of perturbed insulin signaling will shed light on the signicance of leptin signaling in AD development and on the link between obesity and AD. Second, APP transgene appeared to have weight-reducing effects because APP+-ob/ob and APP+-NSY mice were leaner than ob/ob or NSY mice, respectively. Because there was no difference in food intake between each pair of mouse lines, APP transgene may regulate body weight by increasing energy expenditure and/or by reducing food absorption. Further experimental data will be needed to determine the mechanisms involved. Finally, does the T2D-AD connection observed in mice translate to humans? If so, aggressive therapy to control glucose levels in AD patients could prove to be benecial in maintaining cognitive function, despite studies where rosiglitazone appeared to be without effect in several phase III AD trials. Alternatively, pharmacological or lifestyle management of AD patients could also lessen their diabetes burden that, in turn, may slow down AD progression. Epidemiological data might provide answers to these tantalizing possibilities.
ACKNOWLEDGMENTS. Research in the W.H. laboratory is supported by intramural funding from the A*STAR (Agency for Science, Technology and Research) Biomedical Research Council.

17.

18. 19.

20.

21.

22.

sis and targets for therapeutic intervention. Biochem Soc Trans 33:11011105. Farris W, et al. (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 100:41624167. Fewlass DC, et al. (2004) Obesity-related leptin regulates Alzheimers Abeta. FASEB J 18:18701878. Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK3alpha regulates production of Alzheimers disease amyloid-beta peptides. Nature 423:435439. Steen E, et al. (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimers diseaseis this type 3 diabetes? J Alzheimers Dis 7:6380. Ueda H, et al. (1995) The NSY mouse: A new animal model of spontaneous NIDDM with moderate obesity. Diabetologia 38:503508. Sturchler-Pierrat C, et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94: 1328713292.

6558 | www.pnas.org/cgi/doi/10.1073/pnas.1002555107

Han and Li