Alzheimer’s disease (AD) is a public health crisis and growing exponentially as our population ages. The societal and individual burden of Alzheimer’s disease are immense, affecting us socially and economically and threatening the medical system. Praetego is committed to developing effective drug candidates for patients with neurodegenerative diseases associated with aging, starting with Alzheimer’s disease.
The Problem of Glucotoxicity
Glucose (sugar) is the universe fuel for metabolism. As a routine consequence of metabolism, glucose binds with proteins and lipids. This binding produces unstable byproducts (Amadori Intermediates) that are susceptible to oxidative breakdown (glycoxidation and lipoxidation). The breakdown uses redox metal ions (iron, copper) to catalyze this process. Advanced Glycation End-products (AGEs) are the result.
AGEs, often called glycotoxins, cause harm throughout the body as we age. AGE formation is accelerated by hyperglycemic conditions, namely diabetes and related conditions, which occur with increased frequency in aging, and especially in AD. The accumulation of AGEs is linked to oxidative stress, inflammation, cell death, and organ damage.
AGEs, Diabetes, and Neurodegeneration
The role of AGEs in neurodegenerative diseases is well characterized in the scientific literature. As we age, even in the absence of disease, AGEs accumulate in long-lived tissue throughout the body. Likewise, the risk of dementia increases as we age, with age being the greatest risk factor for Alzheimer’s disease, the most common type of dementia. The connection between hyperglycemia, AGEs, and AD is most evident when considering that diabetics are far more likely to develop AD and that diabetes is an established risk factor for Alzheimer’s disease.
AGE pathology affects aging, diabetes, neurodegeneration and Alzheimer’s disease. Further evidence that links the formation of AGE’s with Alzheimer’s disease is that AGE’s accumulate in and promote the formation of the amyloid plaques and neurofibrillary tangles associated with Alzheimer’s disease and related dementias. Through an increasing burden of AGEs in brain tissue, the resultant oxidative stress and mitochondrial dysfunction sets up a feed-forward loop that drives neurodegeneration.
Serious diabetic complications are exacerbated by chronic insults to the vascular system from high blood glucose. One mechanism by which this hyperglycemia causes damage is through fueling the AGE pathway. In addition, growing evidence indicates that in diabetic complications involving the nervous system, specifically Diabetic Peripheral Neuropathy and Retinopathy, neurodegeneration occurs before the microvascular changes.
THE SOLUTION
Amadorins Limit Glucotoxicity
Praetego’s Amadorins are unique upstream inhibitors of the oxidative breakdown of glycated proteins and lipids (glycoxidation and lipoxidation). They casually bind to redox metal ions active and render them unable to catalyze the oxidative reaction. As this chemistry is happening through throughout the body, the Amadorins protect the whole body from oxidative stress and glucotoxicity.
Amadorins Offer a Unique and Comprehensive Mechanism of Action
Praetego’s Amadorins are first-in-class small molecules.
At their core, Praetego’s Amadorins are designed to work systemically to preserve function. This approach could transform the experience of Alzheimer’s disease and other chronic diseases of aging.
