Type 2 diabetic and Alzheimer's disease mice present similar behavioral, cognitive, and vascular anomalies.

Type 2 diabetes (T2D) is considered a major risk factor for Alzheimer's disease (AD). To elucidate the links between both pathological conditions, we compared behavioral and cognitive functions, cerebral amyloid-β peptide (Aβ) levels and vasculature integrity of 11-month-old T2D and AD mice. For this purpose, we performed behavioral tests (open field, object recognition, Y-maze, and elevated plus maze tests), ELISA to assess plasma markers of endothelial/vascular dysfunction, spectrophotometric assays to evaluate cerebral vascular permeability and enzymatic activities, and immunohistochemistry for the assessment of Aβ levels. Both T2D and AD showed similar behavioral and cognitive anomalies characterized by increased fear and anxiety and decreased learning and memory abilities. Interestingly, both groups of animals presented increased plasma markers of endothelial/vascular dysfunction and permeability of cerebral vasculature and impaired mitochondrial enzymatic activities. In addition, a significant increase in Aβ levels was observed in the cortex and hippocampus of T2D mice. These results support the notion that T2D predisposes to cerebrovascular alterations, cognitive decline, and development of AD.

[1]  N. Greig,et al.  Relationship between inflammatory mediators, Aβ levels and ApoE genotype in Alzheimer disease. , 2012, Current Alzheimer research.

[2]  Junjian Zhang,et al.  Cerebral Hypoperfusion and Cognitive Impairment: The Pathogenic Role of Vascular Oxidative Stress , 2012, The International journal of neuroscience.

[3]  S. Correia,et al.  Metabolic Alterations Induced by Sucrose Intake and Alzheimer’s Disease Promote Similar Brain Mitochondrial Abnormalities , 2012, Diabetes.

[4]  E. Ferrannini,et al.  Endothelial dysfunction in type 2 diabetes , 2012, Diabetologia.

[5]  Maurizio Memo,et al.  Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease , 2012, PloS one.

[6]  A. D. de Bem,et al.  Differential effects of insulin on peripheral diabetes-related changes in mitochondrial bioenergetics: involvement of advanced glycosylated end products. , 2011, Biochimica et biophysica acta.

[7]  Hong-Mei Zhang,et al.  Impaired mitochondrial complex III and melatonin responsive reactive oxygen species generation in kidney mitochondria of db/db mice , 2011, Journal of pineal research.

[8]  R. Kessels,et al.  Assessment of working-memory deficits in patients with mild cognitive impairment and Alzheimer’s dementia using Wechsler’s Working Memory Index , 2011, Aging clinical and experimental research.

[9]  N. Castanon,et al.  Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome , 2011, PloS one.

[10]  R. Mayeux,et al.  Type 2 Diabetes and Late-Onset Alzheimer’s Disease , 2011, Dementia and Geriatric Cognitive Disorders.

[11]  H. Hanyu,et al.  Vascular risk factors are associated with faster decline of Alzheimer disease: a longitudinal SPECT study , 2011, Journal of Neurology.

[12]  P. Moreira,et al.  Chronic hypoxia potentiates age-related oxidative imbalance in brain vessels and synaptosomes. , 2010, Current neurovascular research.

[13]  R. Dyck,et al.  Characterization of the 3xTg-AD mouse model of Alzheimer's disease: Part 2. Behavioral and cognitive changes , 2010, Brain Research.

[14]  Myung-Shik Lee,et al.  Role of autophagy in diabetes and mitochondria , 2010, Annals of the New York Academy of Sciences.

[15]  Carlo Caltagirone,et al.  Occurrence of neuropsychiatric symptoms and psychiatric disorders in mild Alzheimer's disease and mild cognitive impairment subtypes , 2010, International Psychogeriatrics.

[16]  G. Perry,et al.  Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia , 2009, Journal of bioenergetics and biomembranes.

[17]  M. Jendrach,et al.  Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice , 2009, Neurobiology of Aging.

[18]  F. Müller-Spahn,et al.  Amyloid-beta Leads to Impaired Cellular Respiration, Energy Production and Mitochondrial Electron Chain Complex Activities in Human Neuroblastoma Cells , 2009, Cellular and Molecular Neurobiology.

[19]  D. Souza,et al.  Caffeine improves adult mice performance in the object recognition task and increases BDNF and TrkB independent on phospho-CREB immunocontent in the hippocampus , 2008, Neurochemistry International.

[20]  M. Lisanti,et al.  ICAM-1: role in inflammation and in the regulation of vascular permeability. , 2008, American journal of physiology. Heart and circulatory physiology.

[21]  J. Growdon,et al.  Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease. , 2008, Archives of neurology.

[22]  D. Fuchs,et al.  Cognitive deterioration in Alzheimer's disease is accompanied by increase of plasma neopterin. , 2007, Journal of psychiatric research.

[23]  A. Sima,et al.  Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes , 2007, Diabetes.

[24]  M. Duchen,et al.  Endothelial Mitochondria: Contributing to Vascular Function and Disease , 2007, Circulation research.

[25]  M. Michalopoulou,et al.  Serum Levels of Soluble Intercellular Adhesion Molecule-1 and Soluble Endothelial Leukocyte Adhesion Molecule-1 in Alzheimer’s Disease , 2004, Journal of geriatric psychiatry and neurology.

[26]  R. Mayeux,et al.  Hyperinsulinemia and risk of Alzheimer disease , 2004, Neurology.

[27]  D. Dickstein,et al.  Blood—Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model , 2003 .

[28]  S. Verma,et al.  New Markers of Inflammation and Endothelial Cell Activation: Part I , 2003, Circulation.

[29]  F. Crawford,et al.  Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. , 2003, Neurological research.

[30]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[31]  E. Baulieu,et al.  The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: Distinct mechanisms? , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Iguchi,et al.  [Cognitive function and brain atrophy in elderly type 2 diabetic patients in comparison with non-diabetic elderly subjects]. , 2001, Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics.

[33]  I. Wicks,et al.  Vascular cell adhesion molecule 1 (CD106): a multifaceted regulator of joint inflammation. , 2001, Arthritis and rheumatism.

[34]  D. Power,et al.  Circulating Leptin Levels and Weight Loss in Alzheimer’s Disease Patients , 2001, Dementia and Geriatric Cognitive Disorders.

[35]  J. Cummings,et al.  Neurobehavioral and neuropsychiatric symptoms in Alzheimer's disease: characteristics and treatment. , 2000, Neurologic clinics.

[36]  M. Le Moal,et al.  Extension of a New Two-Trial Memory Task in the Rat: Influence of Environmental Context on Recognition Processes , 1997, Neurobiology of Learning and Memory.

[37]  J. Cummings,et al.  Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer's disease. , 1996, The American journal of psychiatry.

[38]  A. Sinclair,et al.  Neuropsychological Function in Older Subjects with Non‐insulin‐dependent Diabetes Mellitus , 1995, Diabetic medicine : a journal of the British Diabetic Association.

[39]  M. Le Moal,et al.  A two-trial memory task with automated recording: study in young and aged rats , 1992, Brain Research.

[40]  D. Vestweber,et al.  Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. , 1992, The Journal of biological chemistry.

[41]  T. Frohman,et al.  Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer's disease , 1991, Journal of the Neurological Sciences.

[42]  P. Eikelenboom,et al.  Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family , 1989, Neuroscience Letters.

[43]  Wayne C. Drevets,et al.  Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type , 1989, Biological Psychiatry.

[44]  H. Krebs,et al.  The conversion of citrate into cis-aconitate and isocitrate in the presence of aconitase. , 1952, The Biochemical journal.

[45]  Honglian Shi,et al.  HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells , 2011, Cellular and Molecular Life Sciences.

[46]  M. Petrova,et al.  Endothelial dysfunction and repair in Alzheimer-type neurodegeneration: neuronal and glial control. , 2010, Journal of Alzheimer's disease : JAD.

[47]  Glen E Duncan,et al.  Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[48]  Jacqueline N. Crawley,et al.  Anxiety-Related Behaviors in Mice , 2009 .

[49]  Peter Schönknecht,et al.  Type II diabetes in mild cognitive impairment and Alzheimer's disease: results from a prospective population-based study in Germany. , 2009, Journal of Alzheimer's disease : JAD.

[50]  A. Rauk,et al.  Alzheimer's disease and the 'ABSENT' hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity. , 2005, Medical hypotheses.

[51]  R. Estabrook.  [7] Mitochondrial respiratory control and the polarographic measurement of ADP : O ratios , 1967 .

[52]  Y. Hatefi,et al.  [41] The preparation and properties of DPNH—cytochrome c reductase (complex I–III of the respiratory chain) , 1967 .