Increased Risk of Type 2 Diabetes in Alzheimer Disease

Janson, Juliette; Laedtke, Thomas; Parisi, Joseph E.; O’Brien, Peter C.; Petersen, Ronald C.; Butler, Peter C.

doi:10.2337/diabetes.53.2.474

Cited by 810 publications

(622 citation statements)

References 76 publications

Supporting

Mentioning

579

Contrasting

Unclassified

Order By: Relevance

“…A great deal of interest has been drawn to the role of insulin signaling in the etiology and pathogenesis of AD (54,55). Not only is the type 2 diabetes mellitus a risk factor for AD (56,57), but these two diseases also share several common molecular pathological features such as amyloidogenesis (1, 58 -60) and insulin resistance (54,60,61). Here we show that cultured nerve cells possess a capacity of degrading exogenously added ADDLs in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 88%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

138

101

View full text Add to dashboard Cite

Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

show abstract

Section: Discussionmentioning

confidence: 88%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

138

101

View full text Add to dashboard Cite

show abstract

“…There may be shared predisposition for developing islet amyloid in patients with diabetes and brain amyloid in those with Alzheimer's disease. A population-based clinicopathological study has shown the possible link between neurodegenerative processes that lead to loss of cortical brain cells in Alzheimer's disease and the loss of beta cells in type 2 diabetes [50].…”

Section: Discussionmentioning

confidence: 99%

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. Methods A dementia-free cohort (n=1,248) aged ≥75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and

show abstract

“…Diabetes and Alzheimer disease are risk factors for each other, and it is possible that these two diseases may share common molecular defects (46,47). The Alzheimer disease genes, presenilin-1 and presenilin-2, are key mediators in neurodegeneration (20,47) but their role in ␤-cell degeneration remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Dror¹,

Kalynyak

Bychkivska

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pancreatic ␤-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca 2؉ stores activates calpain-10-dependent apoptosis in ␤-cells. In the present study, we further characterized intracellular Ca 2؉ channel expression and function in human islets and the MIN6 ␤-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca 2؉ flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1␤). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1␤ and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1␤, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in ␤-cells. We demonstrate that this pathway is controlled by Ca 2؉ flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca 2؉ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.

show abstract

Increased Risk of Type 2 Diabetes in Alzheimer Disease

Cited by 810 publications

References 76 publications

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Contact Info

Product

Resources

About