Trends in Pharmacological Sciences
ReviewDoes insulin dysfunction play a role in Alzheimer's disease?
Section snippets
Insulin, DM and AD
DM consists of a group of metabolic disorders that are characterized by hyperglycemia resulting from a defect in either insulin secretion or insulin action. The most common forms are type 1 diabetes [also known as insulin-dependent diabetes mellitus (IDDM)] and type 2 diabetes, which is characterized by insulin resistance [also known as non-insulin-dependent diabetes mellitus (NIDDM)]. In addition to complications that affect the eyes, kidneys, heart, blood vessels and nerves, DM is associated
Insulin activity in the brain and AD: cellular and molecular mechanisms
The role of insulin in the CNS has been little documented compared with its role in muscle and adipose tissue. However, there is evidence that insulin has important functions in brain, including metabolic, neurotrophic, neuromodulatory and neuroendocrine actions. Both insulin and the insulin receptor (IR) are present in the brain, and insulin is actively transported across the blood–brain barrier and might also be produced locally in the brain [24]. IRs are abundant in rodent and human brains
Insulin and AD: a matter of debate
Various aspects of the effects of insulin on the brain remain puzzling. Although several clinical and epidemiological studies indicate a positive effect of insulin on cognitive performance and an increased risk of AD in patients with DM, how insulin modulates cerebral functions, particularly cognitive functions, and the mechanisms that underlie such effects remain largely unexplored. In particular, whether the association between AD and DM is causal or results from shared risk factors such as
Possible therapeutic interventions
The clinical and biological data reviewed here indicate a possible beneficial role of insulin in cognitive function and AD. The possibility that antidiabetic drugs currently used in NIDDM therapy could potentially affect AD pathology has been little explored. It is reported that tolbutamide, a sulfonylurea hypoglycemic agent, might promote amyloid formation by interfering with the binding of Aβ to proteins in the plasma and CSF [63]. Because Aβ and tolbutamide bind to the same site on albumin,
Acknowledgements
We thank E. Ongini (Nicox Research Institute, Milan, Italy) for critical reading of the manuscript. This work was supported by NIH grant AG09464 to P.G. and H.X., and the Alzheimer's Association, the American Health Assistance Foundation and the Ellison Medical Foundation to H.X.
References (68)
Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study
Neurology
(1995)Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study
Br. Med. J.
(1997)Vascular risk and incident dementia: results from a cohort study of the very old
Dement. Geriatr. Cogn. Disord.
(1998)IRS-2 pathways integrate female reproduction and energy homeostasis
Nature
(2000)Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus
J. Neurochem.
(1999)Tracking insulin to the mind
Science
(1998)Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats
J. Biol. Chem.
(1999)- et al.
Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons
J. Biol. Chem.
(1997) Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3β and Fyn tyrosine kinase
J. Neurochem.
(1999)- et al.
Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons
Neuroscience
(2000)
Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme
J. Neurosci.
Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway
FASEB J.
Dementia and its association in type 2 diabetes mellitus: the Fremantle diabetes study
Diabetes Res. Clin. Pract.
Review of alterations in endothelial nitric oxide production in diabetes. Protective role of arginine on endothelial dysfunction
Hypertension
Degradation of soluble amyloid β-peptides 1–40, 1–42, and Dutch variant 1–40Q by insulin degrading enzyme from Alzheimer disease and control brains
Neurochem. Res.
Intraneuronal Aβ42 accumulation in human brain
Am. J. Pathol.
Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease
Lancet
The endocrinology of aging
Science
Post-menopausal estrogen deprivation and Alzheimer's disease
Exp. Gerontol.
Cognition and synaptic plasticity in diabetes mellitus
Trends Neurosci.
Cardiovascular risk factors and cognitive decline in middle-aged adults
Neurology
Analysis of familial and individual risk factors among patients with ischemic vascular dementia and Alzheimer's disease
Angiology
Risk of dementia among persons with diabetes mellitus: a population-based cohort study
Am. J. Epidemiol.
Association of diabetes mellitus and dementia: the Rotterdam study
Diabetologia
Diabetes mellitus and the risk of dementia: the Rotterdam study
Neurology
Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort
Am. J. Epidemiol.
Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance
Neurology
Low blood pressure and blood glucose levels in Alzheimer's disease. Evidence for a hypometabolic disorder?
J. Intern. Med.
Diabetics do not have increased Alzheimer-type pathology compared with aged-matched control subjects – a retrospective postmortem immunocytochemical and histofluorescent study
Neurology
Alzheimer's disease: a study of epidemiological aspects
Ann. Neurol.
Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: a case control study
Neuroepidemiology
Impact of referral bias on clinical and epidemiological studies of Alzheimer's disease
J. Clin. Epidemiol.
Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease
Neurology
Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease
J. Neural Transm.
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