Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The brain mostly uses glucose for energy, but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased, probably owing, at least in part, to oxidative damage to enzymes involved in glycolysis, the tricarboxylic acid cycle and ATP biosynthesis. Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas. We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.

Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease

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

Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal.

Metabolic syndrome, which includes diabetes and obesity, is one of the most widespread medical conditions. It induces systemic inflammation, causing far reaching effects on the body that are still being uncovered. Neuropathologies triggered by metabolic syndrome often result from increased permeability of the blood-brain-barrier (BBB). The BBB, a system designed to restrict entry of toxins, immune cells, and pathogens to the brain, is vital for proper neuronal function. Local and systemic inflammation induced by obesity or type 2 diabetes mellitus can cause BBB breakdown, decreased removal of waste, and increased infiltration of immune cells. This leads to disruption of glial and neuronal cells, causing hormonal dysregulation, increased immune sensitivity, or cognitive impairment depending on the affected brain region. Inflammatory effects of metabolic syndrome have been linked to neurodegenerative diseases. In this review, we discuss the effects of obesity and diabetes-induced inflammation on the BBB, the roles played by leptin and insulin resistance, as well as BBB changes occurring at the molecular level. We explore signaling pathways including VEGF, HIFs, PKC, Rho/ROCK, eNOS, and miRNAs. Finally, we discuss the broader implications of neural inflammation, including its connection to Alzheimer's disease, multiple sclerosis, and the gut microbiome.

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Impact of Metabolic Syndrome on Neuroinflammation and the Blood–Brain Barrier

Alzheimer's disease (AD) is the most common cause of dementia associated with a progressive neurodegenerative disorder, with a prevalence of 44 million people throughout the world in 2015, and this figure is estimated to double by 2050. This disease is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuroinflammation, and hypometabolism; it is related to amyloid-β peptide accumulation and tau hyperphosphorylation as well as a decrease in acetylcholine levels and a reduction of cerebral blood flow. Obesity is a major risk factor for AD, because it induces adipokine dysregulation, which consists of the release of the proinflammatory adipokines and decreased anti-inflammatory adipokines, among other processes. The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists and etiology-based treatments such as secretase inhibitors, amyloid binders, and tau therapies. Strategies for prevention of AD through nonpharmacological treatments are associated with lifestyle interventions such as exercise, mental challenges, and socialization as well as caloric restriction and a healthy diet. AD is an important health issue on which all people should be informed so that prevention strategies that minimize the risk of its development may be implemented.

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Therapies for Prevention and Treatment of Alzheimer’s Disease

Neuroinflammation has emerged as an important cause of cognitive declineduring aging and in Alzheimer’s disease (AD). Chronic low-grade inflammation is observedin obesity and diabetes, which are important risk factors for AD. Therefore, weexamined the markers of inflammation in the brain hippocampal samples of Zucker diabeticfatty (ZDF) rats. Pathway-specific gene expression profiling revealed significantincreases in the expression of oxidative stress and inflammatory genes. Western blotanalysis further showed the activation of NF-kB, defective CREB phosphorylation, anddecreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF,and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology.As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling bloodglucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in thediabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptinincreased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resultedin the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and inthe brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and alsohave the potential to be used in treating Alzheimer’s patients.

Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer’s Disease

Communications between neurons and glial cells play an important role in regulating homeostasis in the central nervous system. cAMP response element-binding protein (CREB), a transcription factor, is down-regulated by neurotoxins, which are known to be released by activated glial cells. To determine the role of CREB signaling in neuroglial interactions, we used three neuroglial coculture models consisting of human neuroprogenitor cell (NPC)-derived neurons and human microglia. Conditioned medium from the Abeta (Aβ)-activated microglia decreased CREB phosphorylation and brain-derived neurotrophic factor promoter activity (47%), whereas the same medium induced (p < 0.01) the promoter of CXCL10, a chemokine, in NPC-derived neuron-rich cultures. These effects were reversed when microglia were exposed to Aβ in the presence of minocycline, an anti-inflammatory agent. The expression of CREB targets, including brain-derived neurotrophic factor, synapsin-1, and BIRC3 decreased by 50-65% (p < 0.01) in neurons isolated by laser capture microdissection in close proximity of microglia in neuroglial mixed cultures. Neuronal survival actively modulated microglial behavior when neurons and microglia were cocultured side-by-side on semicircles of ACLAR membrane. Neuronal injury, caused by the over-expression of dominant negative form of CREB, exacerbated Aβ-mediated microglial activation, whereas CREB over-expression resulted in decreased microglial activation. Decreases in the levels of neuronal markers were observed when NPCs were differentiated in the presence of proinflammatory cytokines IL-1β, tumor necrosis factor α, or IL-6. Instead, the NPCs differentiated into a glial phenotype, and these effects were more pronounced in the presence of tumor necrosis factor α. Our findings suggest that CREB down-regulation is an important component of defective neuroglial communications in the brain during neuroinflammation. Neuroglial interactions were examined using coculture models of human neuroprogenitor cell-derived neurons and microglia isolated from human fetal brain. A novel coculture model of neurons and microglia cultured on ACLAR membranes in the same dish was also included. In this model, over-expression of the dominant negative mutant form of the transcription factor CREB in neurons induced neuronal apoptosis and microglial activation whereas expression of the wild type form of CREB resulted in protection of neurons and suppressed microglial activity, thereby suggesting that neurons play an active role in neuroglial interactions.

LiMei Qin

Papers

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

Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer’s Disease

Regulation of cyclic AMP response element-binding protein during neuroglial interactions.

Dipeptidyl peptidase-4 inhibition in diabetic rats leads to activation of the transcription factor CREB in β-cells.