Although underrecognized, Alzheimer’s disease and related dementias are 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
Advanced Glycation End-products (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 inflammation, cell death, and organ damage. Praetego’s Amadorins inhibit AGE formation at the initial step and could reduce the burden of Alzheimer’s disease and Related Dementias (ADRD), serious diabetic complications, and other diseases associated with aging.
AGE Formation and the Downstream Pathological Consequences
Glucose (sugar) is the universe fuel for metabolism. As a routine part 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 body uses redox metal ions (iron, copper) to catalyze this process. AGEs are the toxic result of the breakdown.
We all generate AGEs as a routine by-product of metabolism. Once formed, AGEs are irreversible. When we are healthy, the body counters AGE damage and suppresses the deleterious effects of AGE accumulation. Advancing age, illness, and acute trauma decrease the body’s ability to manage AGEs. Neurodegeneration and vascular damage are the result. For diabetics, AGE production is amplified due to the excess of available glucose (hyperglycemia).
Research reflects that AGEs have two major pathways with which to instigate damage.
Extracellular AGE activity
As AGEs accumulate outside the cells (extracellular), they aggregate and attract more pro-oxidant activity and generate oxidative stress. They also can become cross-linked and affect the integrity of the extracellular matrix (ECM).
Intracellular AGE activity
When AGEs become attached to receptors on the cell surface, they can incite an inflammatory response. This can result in apoptosis or cell death.
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 tissue throughout the body. Likewise, the risk of dementia (Alzheimer’s disease is the most common form) increases as we age. The connection between hyperglycemia, AGEs, and AD is most evident when considering that diabetics are far more likely to develop AD. Diabetes is an established risk factor for Alzheimer’s disease.
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.
AGEs accumulate in the plaques and 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.
AGE’s are a part of normal aging and, like aging itself, do not necessarily cause neurodegeneration and Alzheimer’s disease, but are significant risk factors.
The metabolism of glucose produces AGEs.
Diabetics have greater source of fuel and therefore, a higher risk of developing AD.
THE SOLUTION
Amadorins Inhibit AGE Formation
Praetego’s Amadorins are upstream inhibitors of the oxidative breakdown of glycated proteins and lipids (glycoxidation and lipoxidation). They bind to the redox metal ions driving oxidation and render them unable to catalyze the reaction. The key is not removing these metal ions completely, a process called chelation, as redox metal ions are necessary for normal biochemical activity.
The Amadorins are unique from traditional pharmacotherapy as they do not bind to specific protein receptors. Instead, with sufficient circulating plasma levels, they mediate the toxic biochemical breakdown of byproducts in glucose metabolism, which otherwise trigger a pathological cascade. In this manner, they provide systemic biological protection.
Amadorins Offer a Unique and Comprehensive Mechanism of Action
Praetego’s Amadorins are highly potent 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.
Literature links to research on AGE pathology, Diabetes, and Alzheimer’s disease
Age- and Stage-dependent Accumulation of Advanced Glycation End Products in Intracellular Deposits in Normal and Alzheimer’s Disease Brains.
Luth et al. Cerebral Cortex February 2005;15:211–220
https://doi:10.1093/cercor/bhh123
Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury.
Rungratanawanich et al. Experimental & Molecular Medicine (2021) 53:168–188
https://doi.org/10.1038/s12276-021-00561-7
Ne-CARBOXYMETHYLLYSINE IN BRAIN AGING, DIABETES MELLITUS,
AND ALZHEIMER’S DISEASE
Girones et al. Free Radical Biology & Medicine, Vol. 36, No. 10, pp. 1241 – 1247, 2004
https://doi:10.1016/j.freeradbiomed.2004.02.006
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease.
Butterfield A and Halliwell B.
https://doi.org/10.1038/s41583-019-0132-6
Cognitive decline and dementia in diabetes: mechanisms and clinical implications.
Biessels GJ and Despa F. Nat Rev Endocrinol. 2018 October ; 14(10): 591–604. https://doi:10.1038/s41574-018-0048-7
Alzheimer’s disease and type 2 diabetes mellitus: A systematic
review of proteomic studies.
Pereira JD et al. Journal of Neurochemistry. 2021;156:753–776.
Advanced glycation end products and protein carbonyl levels in plasma reveal sex-specific differences in Parkinson’s and Alzheimer’s disease.
Sharma et al. Redox Biology 34 (2020) 101546
https://doi.org/10.1016/j.redox.2020.101546
