issue Research 2024

Through the Microscope: The Impact of Diabetes on Neurodegeneration

Grace E. Stutzmann, PhD, director, Center for Neurodegenerative Disease and Therapeutics

Grace E. Stutzmann, PhD, director, Center for Neurodegenerative Disease and Therapeutics

The “on ramp” to a diagnosis of Alzheimer’s disease (AD) is likely long, slow and insidious, with many intervening factors that can alter its course along the way. While we don’t know what specifically causes AD, we are improving our understanding of risk factors that can accelerate or divert that trajectory. While some of these are gene-based (ApoE4 alleles, Down syndrome/trisomy 21, APP mutations), and thus little we can do to change them, others reflect lifestyle and environmental influences that do allow for interventions. And some are likely interactions of both. Diabetes would fall into this category, and is increasingly recognized as a significant AD risk factor, so much so that it has an unofficial moniker of “Diabetes Type 3.” As the adult brain accounts for 20–25% of total body resting glucose consumption, and insulin has other regulatory roles in the brain, diabetes introduces an immense stressor that can trigger a host of AD-related cascades including the synaptic deficits that underlie memory impairments.

Judith A. PotashkinJudith A. Potashkin, PhD, investigator, Center for Neurodegenerative Disease and Therapeutics

Molecular, epidemiological and clinical studies have revealed that diabetes is associated with an increased risk and progression of AD and Parkinson’s disease (PD), but may confer neuroprotection against amyotrophic lateral sclerosis (ALS) in elderly individuals. These studies show that targeting the insulin signaling pathway using commonly prescribed antidiabetic drugs may elicit neuroprotection in AD, PD and ALS. In the absence of disease-modifying agents for neurodegenerative diseases, clinical trials have shown that implementation of lifestyle modifications such as a Mediterranean diet, exercise, restorative sleep, stress reduction, social support and the elimination of toxic environmental factors may reduce the risk for AD and PD. In addition, high-calorie diets may be beneficial for early-stage ALS patients.

Marc GlucksmanMarc Glucksman, PhD, director, Center for Proteomics and Molecular Therapeutics

The Midwest Proteome Center and Glucksman Laboratory use proteomic-based biomarker discovery strategies for targeting disease-specific molecules that guide novel therapies. Our distinct research projects involve diabetic foot ulcers and neurodegenerative diseases (Alzheimer’s, Parkinson’s). Further delineation of biomarkers common to both disorders is needed. Diabetes and neurodegeneration have associated inflammatory biomarkers. Additionally, insulin resistance and insulin-like factors in the brain may contribute to Alzheimer’s. The emerging use of the moniker “Type 3 diabetes” underscores this suspected role in age-related cognitive decline. Thus, our “big data” technology-based approaches can potentially elucidate convergent pathways of disease progression, diagnosis, prognosis and future treatments.

Holly HunsbergerHolly Hunsberger, PhD, investigator, Center for Neurodegenerative Disease and Therapeutics

AD is multi-faceted, and because each individual has a different life experience, scientists have yet to determine the “cause.” Most likely, there will not be a “cure-all,” but a combination therapy targeting multiple pathways. The Hunsberger Lab examines the AD exposome, meaning we are trying to understand how lifestyle, drugs, biological sex and social interaction impact AD progression. Discovering early-stage behavioral and brain-wide circuit changes prior to disease pathology and cognitive decline is key to developing successful and potentially personalized therapeutics. Interestingly, Type 2 diabetes increases your risk of AD by 56%, as recent work shows amyloid, a hallmark protein of AD, in the blood of people with early-onset diabetes. The processing and clearing of amyloid is also related to insulin signaling, and thus could be a potential connection between AD and diabetes. Therefore, diet and lifestyle should be considered major factors contributing to the progression of diabetes and AD.

Perspectives expressed in "Through the Microscope" columns are solely those of the authors and are not intended to represent those of ĪŽĀėČŗ½».

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