Purpose

Caring for Alzheimer’s disease and related dementias threatens to overwhelm us socially, emotionally, and financially as our population ages. Praetego is committed to developing effective drug candidates for patients with neurodegenerative diseases associated with aging, starting with Alzheimer’s disease. We call our drugs the Amadorins.


 

THE PROBLEM

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, due to the excess of available glucose (hyperglycemia), AGE production is amplified.

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 in 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 feeding the AGE pathway. However, there is a growing body of evidence indicating that neurodegeneration occurs before microvascular changes in certain serious diabetic complications. This is apparent in research conducted on Diabetic Peripheral Neuropathy and Retinopathy.

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.

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 them completely, a process called chelation, as redox metal ions are necessary for normal biochemical activity. The Amadorins circulate in plasma addressing AGE-mediated pathology from released metal ions.

The Amadorins are unique from traditional pharmacotherapy since they do not bind to specific protein receptors. By addressing the triggering pathology via chemical intervention, 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.

https://DOI:10.1111/jnc.15166

 

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