ReviewInsulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis
Introduction
The United States Census Bureau projects that between 2005 and 2025 the total population will grow 20%, but the demographic of age 65 and over will increase by nearly 50%. As the population ages, type 2 diabetes and Alzheimer's disease (AD) are becoming surging epidemics. Both diseases are chronic and complicated, and they are the leading causes of morbidity and mortality in the elderly [88]. Several epidemiology studies have shown that type 2 diabetes increased the risk of AD in both cross-sectional and prospective populations. Further, elevated peripheral insulin, a common biomedical sign of type 2 diabetes, has been singled out as a possible independent risk factor of AD.
To date, it has been found that the Apolipoprotein E4 (ApoE4) allele is a major risk factor of late-onset AD [85]. However, 50% of AD patients do not possess ApoE4; other risk factor(s) might contribute to the pathogenesis of the disease. In the process of elucidating other contributing factors the association between hyperinsulinaemia and AD was found to be particularly strong in populations lacking ApoE4. While the mechanism behind such a relationship is still unclear, it is noted that the two diseases share a common protease, insulin-degrading enzyme (IDE). This review will summarize the relevant data on the relationship of type 2 diabetes and hyperinsulinaemia with AD. We will also present current researches indicating a relationship among IDE and the two diseases.
Section snippets
Type 2 diabetes and Alzheimer's disease
Cross-sectional studies in epidemiology using different large populations have shown that the percentage of type 2 diabetes among AD patients is significantly higher than among age-matched non-AD controls [49], [67], [83]. At the same time, type 2 diabetes patients are also shown to suffer more from cognitive impairment, lower Mini-Mental Status Exam (MMSE) score and lower rate of correct Clock Drawing Test (numbers and hands), as compared with the non-diabetic subjects [80].
In longitudinal
Hyperinsulinaemia and the risk of Alzheimer's disease in the absence of ApoE4
In the pre-clinical syndrome of type 2 diabetes, hyperinsulinaemia precedes hyperglycemia by many years [93], and as a result, the insensitivity of the insulin receptor or the defect of signal transduction, probably due to chronic over-stimulation, is considered to be the cause of the disease. After the onset of type 2 diabetes, hyperinsulinaemia is present among many but not all diagnosed cases [50]. Several studies have shown that insulin concentrations in serum were higher among AD patients
Insulin-degrading enzyme
There are probably several mechanisms underlying the relationship between type 2 diabetes and the increased risk of AD. For example, the formation of advanced glycation end product (AGE) in diabetes has been shown to be aggregated with Aβ in plaques of AD brain. Diabetes also causes cerebrovascular changes that are associated with AD [20] (reviewed by de la Torre). However, these could not explain that elevated insulin itself without the clinical syndrome of type 2 diabetes is strongly related
Insulin-degrading enzyme degrades insulin, amylin and amyloid-β peptide
To date, all the identified genes with missense mutations that predispose an individual to AD either increase Aβ production or enhance Aβ fibrillation. The actual amount of neurotoxic Aβ in the brain is determined by (1) Aβ production through Amyloid Precursor Protein (APP) processing and (2) Aβ degradation and clearance. Several proteases are involved in Aβ degradation in vitro, but the two major enzymes in vivo are IDE and Neprilysin (NEP) [54].
Several short peptides with molecular weights of
Genetic variation of IDE has been associated with AD as well as type 2 diabetes
Recent genetic studies have shown that chromosome 10 contains potentially important novel gene(s) for late-onset AD as well as type 2 diabetes [21], [22], [64], [86]. Since the IDE gene is located on chromosome 10 [11], and IDE demonstrates an ability to degrade insulin, amylin and Aβ, it is reasonable to hypothesize that IDE as a candidate gene for both type 2 diabetes and AD.
Several association studies using a single nucleotide polymorphism (SNP) approach have investigated the relationship
Summary and future research
IDE degrades both insulin and amylin, which are related to type 2 diabetes; it also degrades Aβ, a peptide involved in AD pathology. The enzyme activity, including substrate affinities, presents a logical mechanism for the fact that hyperinsulinaemia and type 2 diabetes increase the risk of AD in elderly. We hypothesize that the deficiency of IDE, which leads to increased Aβ and thus AD pathology in the brain, can be a result of either diversion of IDE from the metabolism of Aβ to the
Acknowledgments
W.Q.Q. thanks Dr. Dennis J. Selkoe for his encouragement to pursue the idea of Aβ degradation then the IDE work when she worked in his laboratory, and for his continuous support. The authors thank Peg AtKisson, Igna Peter, Timothy Liu, Drew Leins and Jacqui Yee for critically reading and editing the manuscript. This work was supported in part by grants from NIA, AG-022476 for W.Q.Q., AG-21790 for M.F.F., and by grants from GREFF award (GCRC of New England Medical Center) and NEMC recruitment
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