Diabetes Causes Accumulation of Amyloid Beta Oligomers in a New Animal Model of Alzheimer's Disease Neuropathology


Invention Summary:

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that affects over 15 million people worldwide and it is expected to quadruple by 2050. In order to understand the molecular basis of AD, many animal models have been developed. They range from invertebrates like the fruit fly to large mammals such as primates[1] with each model having its set of strengths and limitations. However, to date, studying Alzheimer pathophysiology and the root causes of AD has not been really possible in these models. 

The use of rodent models is standard in the study of AD and the drug discovery process but they are limited in their application in AD because they do not produce the amyloid-b (Ab) peptides with the same amino acid sequence as humans. As such, they require genetic manipulations that by their nature obviate normal physiological and stress responses that are key in Alzheimer protein biology and disease.

In contrast, rabbits express Ab peptides with a sequence identical to the human sequence. This genetically normal animal model is key, since it allows normal interplay between potentially synergistic or antagonistic disease mechanisms characterized for AD.  The hypercholesterolemia rabbit model for AD is created by feeding them a diet of high cholesterol for an extended period of time.[2] However, to date the brains of these rabbits showed limited AD like neuropathology.

We have identified and characterized this model of Alzheimer pathology that not only reproduces hallmark features of AD in brain, but also in muscle to model IBM, inclusion body myositis, the major age dependent degenerative disease of muscle, and the lens (cataract). This model allows testing and development of therapeutics and diagnostics, but critically allows analysis of collateral effects in organs and tissues throughout the body.

The invention consists of a new rabbit model for AD that better resembles the pathology found in humans.  In addition, researchers at Rutgers have shown a direct relationship between AD and diabetes. By using genetically unmodified rabbits, then showed that insulin deficiency causes pathological increase in expression of Ab and production of small neurotoxic Ab oligomer accumulation in brain regions fundamentally involved in memory and cognition.  Widespread deposits of Ab and neurotoxic Ab small soluble oligomers were found in both of these key brain areas. Receptors for advanced glycation end products (RAGE) also known to avidly bind Ab were also expressed. Critically, this model also reproduced Tau microtubule associated protein pathology, with increased Tau phosphorylation, extensively associated with neurodegeneration and brain stress. Many Alzheimer disease mechanisms have been identified with potentially synergistic and antagonistic interactions, and here, with our new model we can analyze their composite effects without inherently predisposing any one process.

Market Applications

  • Animal model to be used in the evaluation of new therapeutics for Alzheimer’s
  • Application for evaluation of diagnostic methods.

Advantages:

  • Novel Alzheimer’s rabbit model that links diabetes with Alzheimer’s
  • Model is easy to generate
  • Produces hallmark Alzheimer protein pathology in tissues outside the brain that also produce characteristic Abeta pathology

Publications:

[1] Woodruff-Pak, D.S; Journal of Alzheimer’s Disease 15 (2008), 507-521

[2] Ghribi, O.; Journal of Alzheimer’s Disease,15 (2008), 673-684

Rutgers ID: S10-16
Category(s):
Life Sciences
Research Tools
Contact:
Yong Zhang
Licensing Manager
848-932-4523
yong.zhang@rutgers.edu
Inventors:
Peter Frederikse
Chinniswamy Kasinathan
Keywords:
CNS
Drug Screening