Connections between diabetes and Alzheimer’s disease explored
28 May 2009
Modern societies face the increasing burden of age-related diseases,
in particular Alzheimer’s disease (AD) and type 2 diabetes (T2D). There
is some evidence that the causes underlying both diseases are linked.
Do AD and T2D represent the endpoint of aged, exhausted, and
dysfunctional cells having reached their maximal life expectancy or are
AD and T2D the consequences of living in superabundance including
excessive food supply, work demands, psychosocial stress, and an
excessive sedentary life style?
In a special issue of the Journal of Alzheimer’s Disease
(April 2009), nineteen contributions examine the possible connections
between AD and T2D.
Numerous epidemiological studies have described the incidence of both
AD and T2D in the Western world and extensively deﬁned common
environmental risk factors.
Guest Editors Angelika Bierhaus and Peter P. Nawroth, both of the
University of Heidelberg, have assembled a group of prominent
investigators to explore the connections between AD and T2D pathologies
using literature reviews of current human studies, overviews of animal
models, reviews of basic pathophysiology findings, and biochemical
In the introduction Bierhaus and Nawroth note that several
pathological features have been identified as common denominators of AD
and T2D including impaired glucose/energy metabolism, altered insulin-signaling
pathways, mitochondrial dysfunction, oxidative stress, and inflammation.
Daniel Kopf and Lutz Frölich report a systematic review of fourteen
studies that examined the risk of incident Alzheimer’s disease in
diabetic patients. All studies reported risk ratios greater than one
with four studies showing statistically significant excess risk.
Pablo Toro, Peter Schönknecht, and Johannes Schröder follow with the
results of a study of almost 200 subjects born between 1930 and 1932.
For those with either mild cognitive impairment (MCI) or with AD, there
was an increased tendency for T2D.
José A. Luchsinger and Deborah R. Gustafson present a comprehensive
review of the epidemiologic evidence linking the continuum of adiposity
and T2D with AD.
The mechanisms relating adiposity and T2D to AD may include
hyperinsulinemia, advanced products of glycosylation, cerebrovascular
disease, and products of adipose tissue metabolism.
The implication of these associations is that a large proportion of
the world population may be at increased risk of AD given the trends for
increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D.
However these associations may also present a unique opportunity for
prevention and treatment of AD.
Ceramides are a type of lipid molecule that are both neurotoxic and
causes insulin resistance. Ming Tong and Suzanne M. de la Monte report
on their investigation of the role of ceramides as mediators of
neurodegeneration using an in vitro culture model.
Exposure to two different ceramides impaired energy metabolism,
viability, and insulin and insulin-like growth factor signaling
mechanisms, and resulted in increased levels of AβPP-Aβ and pTau, while
an inactive ceramide analogue had no significant effect on these
Following this line of investigation, Lascelles E. Lyn-Cook, Jr.,
Margot Lawton, Ming Tong, Elizabeth Silbermann, Lisa Longato, Ping Jiao,
Princess Mark, Jack R. Wands, Haiyan Xu and Suzanne M. de la Monte used
pairs of mice fed a high-fat diet (HFD) or a normal diet and found that
mild neurodegeneration and brain insulin resistance resulted from the
They found that ceramide production increased in the HFD mice and
that obesity, T2D and nonalcoholic steatohepatitis (NASH) might all be
mediated by the excess ceramides.
In the area of possible therapies for AD, Nikolaos Tezapsidis, Jane
M. Johnston, Mark A. Smith, J. Wesson Ashford, Gemma Casadesus, Nikolaos
K. Robakis, Benjamin Wolozin, George Perry, Xiongwei Zhu, Steven J.
Greco, and Sraboni Sarkar write about a possible use of leptin to reduce
the affects of AD. They speculate that a deficiency in leptin levels or
function may contribute to systemic and central nervous system
abnormalities leading to AD.
Three articles focus on the role of oxidative stresses and the
development of AD. Paula I. Moreira, Ana I. Duarte, Maria S. Santos, A.
Cristina Rego, and Catarina R. Oliveira write about the processes
underlying the pathogenesis of Alzheimer’s disease, including impaired
glucose/energy metabolism, mitochondrial dysfunction, oxidative stress
and altered insulin-signaling pathways.
V. Prakash Reddy, Xiongwei Zhu, George Perry, and Mark A. Smith
discuss how oxidative stress plays a major role in diabetes as well as
in Alzheimer’s disease and other related neurological diseases. The
advanced glycation end products and lipid peroxidation products are
ubiquitous to diabetes and Alzheimer’s disease and serve as markers of
disease progression in both disorders.
Sajjad Muhammad, Angelika Bierhaus, and Markus Schwaninger review
some recent findings on the role of reactive oxygen species in
diabetes-induced vascular dysfunction and the consequent cerebral
ischemia and compare them with key findings in AD.
Allan Jones, Philipp Kulozik, Anke Ostertag, and Stephan Herzig
review common metabolic and inflammatory processes implicated in the
pathogenesis of both T2D and AD. In particular, they emphasize the role
of critical transcriptional checkpoints in the control of cellular
metabolism, insulin sensitivity, and inflammation.
These transcriptional regulators might hold great promise as new
therapeutic targets in the potentially combined treatment of type 2
diabetes and Alzheimer’s disease.
Other inflammatory processes might be involved in both AD and T2D.
Ivica Granic, Amalia M. Dolga, Ingrid M. Nijholt, Gertjan van Dijk, and
Ulrich L. M. Eisel investigate how both inflammation and the inducible
nuclear factor NF-κB might be involved in both diabetes mellitus and
Alzheimer's disease. Clement T. Loy and Stephen M. Twigg discuss how
advanced glycation end products (AGEs) and growth factor dysregulation
may link diabetes and AD.
Receptor for Advanced Glycation Endproducts (RAGE) is a superfamily
of cell molecules which serves as a receptor for amyloid-β peptide (Aβ).
Increased expression of RAGE is observed in regions of the brain
affected by Alzheimer’s disease (AD), and Aβ-RAGE interaction in vitro
leads to cell stress with the generation of reactive oxygen species and
activation of downstream signaling. Shi Du Yan, Angelika Bierhaus, Peter
P. Nawroth, and David M. Stern suggest that RAGE may be a therapeutic
target for AD.
Masayoshi Takeuchi and Sho-ichi Yamagishi contribute a study of Toxic
Advanced Glycation End-products (TAGE). These AGEs can cause oxidative
stress in numerous types of cells, which could contribute to the
pathological changes of diabetic vascular complications and AD.
Akihiko Taguchi discusses how RAGE-mediated chronic inflammation can
initiate a degenerative positive feedback loop between endothelium and
neuronal cells. Elzbieta Kojro and Rolf Postina explore how RAGE and
Amyloid-beta protein precursor (AβPP) proteolysis can be affected by
insulin and how proteolysis of RAGE may prevent transport of Aβ across
the blood-brain barrier.
A contributing factor to oxidative stress can be excess free iron.
Sandro Altamura and Martina U. Muckenthaler review experimental
evidences for an involvement of iron in Alzheimer’s disease and
Parkinson’s disease. They also propose a role for iron in
atherosclerosis, another frequent disorder of aging.
Michael Morcos and Harald Hutter report that the classical model
organism in aging research, the nematode Caenorhabditis elegans (C.
elegans), shares many similarities at the molecular level to
pathological processes found in humans. C. elegans has an accessible and
well characterized nervous system and features several genes homologous
to human genes implicated in AD like amyloid-β protein precursor,
presenilins and tau.
1. Journal of Alzheimer's Disease, 16:4 (April 2009) published by IOS
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