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Review
. 2017 May;1863(5):1037-1045.
doi: 10.1016/j.bbadis.2016.04.017. Epub 2016 May 6.

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

Subbiah Pugazhenthi  1 , Limei Qin  2 , P Hemachandra Reddy  3
Affiliations
Review

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

Subbiah Pugazhenthi et al. Biochim Biophys Acta Mol Basis Dis. 2017 May.

Abstract

Cognitive decline in chronic diabetic patients is a less investigated topic. Diabetes and obesity are among the modifiable risk factors for Alzheimer's disease (AD), the most common form of dementia. Studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders. Advanced glycation end products generated by chronic hyperglycemia and their receptor RAGE provide critical links between diabetes and AD. Peripheral inflammation observed in obesity leads to insulin resistance and type 2 diabetes. Although the brain is an immune-privileged organ, cross-talks between peripheral and central inflammation have been reported. Damage to the blood brain barrier (BBB) as seen with aging can lead to infiltration of immune cells into the brain, leading to the exacerbation of central inflammation. Neuroinflammation, which has emerged as an important cause of cognitive dysfunction, could provide a central mechanism for aging-associated ailments. To further add to these injuries, adult neurogenesis that provides neuronal plasticity is also impaired in the diabetic brain. This review discusses these molecular mechanisms that link obesity, diabetes and AD. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Keywords: Advanced glycation end products; Alzheimer's disease; Diabetes; Inflammation; Mitochondria; Obesity; Oxidative stress.

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Figures

Figure 1
Figure 1. Common pathways of aging-associated disorders
The risk of Alzheimer’s disease (AD) in elderly individuals is increased by other aging-associated comorbidities including obesity, diabetes and cardiovascular impairment. Oxidative stress, mitochondrial dysfunction and chronic inflammation observed in these conditions are also some of the important causes of AD.
Figure 2
Figure 2. Pathways of neurodegeneration in the diabetic brain
Neurodegeneration in Alzheimer’s disease is caused by the formation of neurofibrillary tangles and the deposition of extracellular β amyloid plaques. Both pathways are facilitated by insulin resistance, the major cause of type 2 diabetes. Chronic hyperglycemia-generated advanced glycation end products (AGEs), oxidative stress and neuroinflammation are also important causes of neurodegeneration, thus providing critical links between diabetes and AD.
Figure 3
Figure 3. Causes and consequences of mitochondrial dysfunction
Multiple factors are known to cause mitochondrial dysfunction. These factors include aging, increased free fatty acids, hyperglycemia, polymorphisms and DNA mutations in mitochondrial genome and mutant protein(s) association with mitochondria. Dysfunctional mitochondria produce reduced ATP, decreased biogenesis, impaired β-oxidation and increased reactive oxygen species. These events may contribute to diabetes, obesity and insulin resistance ultimately causing Alzheimer’s disease in elderly individuals.
Figure 4
Figure 4. Neuroinflammation in the Diabetic brain
Brain inflammation in diabetes is considered to result from peripheral inflammation. Cytokines produced by macrophages can pass through the blood brain barrier (BBB). However the less understood area is the potential direct effects of saturated fatty acids (SFA) and advanced glycation end products (AGEs) on neurons astrocytes and microglia, the resident macrophages of the brain. Increased uptake of fatty acids by the brain in metabolic syndrome has been reported. Neurotoxins generated by astroglia cause injuries to neurons. Stress signals released by dying neurons can further activate the glial cells, thus leading to a vicious cycle. Activators of SIRT1 have two beneficial therapeutic actions, namely, increasing neuronal mitochondrial biogenesis and anti-inflammatory action in glial cells.
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