Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis

• Published in: Neurobiology of aging 2006-02, Vol.27 (2), p.190-198
• Main Authors: Qiu, Wei Qiao, Folstein, Marshal F.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Amyloid β-peptide; Animals; Apolipoprotein E4; Apolipoproteins E - metabolism; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Humans; Hyperinsulinism - metabolism; Insulin; Insulin - metabolism; Insulin-degrading enzyme; Insulysin - genetics; Insulysin - metabolism; Medical sciences; Models, Biological; Neurology; Risk; Type 2 diabetes and Alzheimer's disease
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2005.01.004

Clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increased the risk of developing Alzheimer's disease (AD) in the elderly. The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-β peptide (Aβ), a short peptide found in excess in the AD brain. We review the current evidence, which suggests that hyperinsulinaemia may elevate Aβ through insulin's competition with Aβ for IDE. Genetic studies have also shown that IDE gene variations are associated with the clinical symptoms of AD as well as the risk of type 2 diabetes. The deficiency of IDE can be caused by genetic variation or by the diversion of IDE from the metabolism of Aβ to the metabolism of insulin. It is intriguing to notice that both hyperinsulinaemia and IDE gene variations are related to the risk of AD when the Apolipoprotein E4 (ApoE4) allele, the major risk factor of late-onset AD, is not present. Further studies of the role of IDE in the pathogenesis of AD, which may uncover potential treatment target, are much needed.