Elsevier

Brain Research Reviews

Volume 56, Issue 2, December 2007, Pages 384-402
Brain Research Reviews

Review
Common pathological processes in Alzheimer disease and type 2 diabetes: A review

https://doi.org/10.1016/j.brainresrev.2007.09.001Get rights and content

Abstract

Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) are conditions that affect a large number of people in the industrialized countries. Both conditions are on the increase, and finding novel treatments to cure or prevent them are a major aim in research. Somewhat surprisingly, AD and T2DM share several molecular processes that underlie the respective degenerative developments. This review describes and discusses several of these shared biochemical and physiological pathways. Disturbances in insulin signalling appears to be the main common impairment that affects cell growth and differentiation, cellular repair mechanisms, energy metabolism, and glucose utilization. Insulin not only regulates blood sugar levels but also acts as a growth factor on all cells including neurons in the CNS. Impairment of insulin signalling therefore not only affects blood glucose levels but also causes numerous degenerative processes. Other growth factor signalling systems such as insulin growth factors (IGFs) and transforming growth factors (TGFs) also are affected in both conditions. Also, the misfolding of proteins plays an important role in both diseases, as does the aggregation of amyloid peptides and of hyperphosphorylated proteins. Furthermore, more general physiological processes such as angiopathic and cytotoxic developments, the induction of apoptosis, or of non-apoptotic cell death via production of free radicals greatly influence the progression of AD and T2DM. The increase of detailed knowledge of these common physiological processes open up the opportunities for treatments that can prevent or reduce the onset of AD as well as T2DM.

Introduction

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders, and its prevalence increases with age. Insulin resistance or T2DM is often associated with the most commonly occurring metabolic and physiologic problems, including elevated blood pressure, cardiovascular disease, dyslipidemia (high triglyceride levels and low levels of high-density lipoproteins), and high cholesterol levels. Together with visceral obesity, this clustering of risk factors is known as the metabolic syndrome (Ahmed and Goldstein, 2006, Levine, 2006). Recent evidence has identified T2DM as a risk factor of Alzheimer's disease (AD). AD, a progressive neurodegenerative disorder of hitherto unknown etiology leading progressively to severe incapacity and death, has been described as the pandemic of the 21st century (Jellinger, 2006). Familial AD is caused by mutations in the amyloid precursor protein (APP) and presenilin genes, both linked to Aβ synthesis. The etiology of the sporadic form of Alzheimer's disease (SAD) is complex, with an interaction of both genetic and environmental risk factors (Blennow et al., 2006). A key event in AD pathogenesis is the conversion of Aβ from its soluble monomeric form into various aggregated forms in the brain. Preventing aggregation of Aβ is being actively pursued as one therapeutic strategy for treating AD (Liu et al., 2005).

Section snippets

Similarities between physiological processes underlying T2DM and AD

Several studies have shown that there are many similarities between T2DM and AD, and that both conditions underlie common physiological processes. These include aging-related processes, degeneration, high cholesterol levels, metabolic disorders and degenerative processes, β-amyloid aggregation, and also second messenger system abnormalities such as glycogen synthase kinase 3 (GSK3) overactivity, and deregulated protein phosphorylation (Doble and Woodgett, 2003, Ristow, 2004), association with

Epidemiological studies that link T2DM and AD

Numerous epidemiological studies have linked T2DM with an increased risk of developing AD (Haan, 2006). Recent evidence from a population-based study shows a link between T2DM and AD, with an incidence of AD as much as 2 to 5 times higher in population suffered from T2DM. Four risk factors (T2DM, hypertension, heart disease, and smoking) were attributed to a higher risk of AD. The risk of AD increased with accumulation of the associated risk factors (Luchsinger et al., 2005). An investigation

Similarities between T2DM and AD: 1. Amyloid peptides

There is considerable evidence to suggest that the accumulation of Aβ is the cause of the neurodegeneration that occurs in AD (Hölscher, 2005, Small and Cappai, 2006). Similarly, loss of β cells in pancreas in T2DM is partly attributed to amyloid deposits in the islets (Clark et al., 1988). Aβ is a product from the cleavage of its precursor protein, APP. Similarly, islet amyloid is derived from islet amyloid polypeptide (IAPP) (Cooper et al., 1987). The 90% structural similarity between APP and

Similarities between T2DM and AD: 2. NFTs and hyperphosphorylated tau protein

Another pathologic hallmark of AD is the accumulation of intracellular neurofibrillary tangles (NFTs), containing a hyperphosphorylated form of tau protein. The activation of insulin receptors triggers tau phosphorylation: increasing the peripheral insulin level by insulin injection significantly increased tau phosphorylation at Ser202 in the brain within 10 min (Freude et al., 2005). Further, this study reported that insulin receptor signalling and tau phosphorylation was completely abolished

Similarities between T2DM and AD: 3. Insulin and AD

There is growing evidence that impairments in insulin signalling is partly responsible for the cognitive decline in AD (de la Monte and Wands, 2005, Gasparini and Xu, 2003, Watson and Craft, 2004). One impairment that has been described repeatedly is the observation that in AD, insulin resistance in the CNS develops due to alterations of insulin receptor sensitivity. This affects the expression and metabolism of Aβ and tau protein. Insulin and the insulin receptor (IR) are abundantly expressed

Similarities between T2DM and AD: 4. Glyceraldehyde-derived advanced glycation end products (AGEs) and O-linked N-acetylglucosamine acylation

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that have side groups irreversibly added to them. AGEs are created from reactive derivatives by non-enzymatic glucose–protein condensation reactions, as well as from lipids and nucleic acids exposed to reducing sugars such as glucose (Yamagishi et al., 2002). In fact, the term AGEs is now used for a broad range of advanced products of the glycation process (also called the “Maillard reaction”). The product can form

Basic structure and biological activity of TGFs

The Transforming growth factor group (TGF) has been identified two decades ago (Border and Noble, 1994). TGF and its receptor have been found in virtually every cell in the body, including epithelial, endothelial, hematopoietic, neuronal, and connective tissue cells (O'Connor-McCourt et al., 1987, Yamaguchi et al., 1990, Ziyadeh, 1994). The TGF group includes four major families: the Mullerian inhibitory substance (MIS) family, the inhibin/activin family, the bone morphogenetic protein (BMP)

Similarities between T2DM and AD: 6. Evidence from animal models

Common processes that underlie both T2DM and AD are further shown by animal models of AD and diabetes. Various experimental models of AD have been developed, but none has been found to be truly representative of the sporadic type of AD (SAD), which cannot be directly linked to a specific gene or mutation. Taken that SAD has now been recognized as an insulin-resistant brain state, it has been proposed that rats injected with streptozotocin (STZ) directly into the brain could be used as an

Conclusion

The presented evidence highlights the wide range of common molecular mechanisms of degeneration that link T2DM with AD. While there are obvious differences between these two conditions, it is important to note the similarities in protein misfolding, insulin signalling impairments, and cytotoxic processes found in both diseases. Research to obtain detailed knowledge about the precise molecular processes can be of great help in the development of novel treatments and drug targets which can be of

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