Research Findings

We are pleased to provide updates from previous CART Fund grant recipients outlining the results of their research. We are encouraged by these researchers’ continued efforts to provide cutting-edge research data at world-class facilities in the United States thanks to grants from The CART Fund.

Final Reports from 2016 Grant Recipients:

Dr. Frank Sharp (University of California at Davis) was the recipient of a $125,000 grant from The CART Fund.

We were the first to propose that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer’s disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1-42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

Posted October 23, 2018

 

 

Dr. Yueming Li (Memorial Sloan Kettering Cancer Center, NYC) was the recipient of a $250,000 grant from The CART Fund.

Alzheimer’s disease (AD) is characterized by an aggregation of toxic proteins that build up in the brain. Normally, a process called autophagy allows cells to rid themselves of any “garbage” they hold. We define that garbage as proteins that are unnecessary or dysfunctional components.

When people have AD, the autophagy process fails with two specific proteins, toxic amyloid beta plaques and tau tangles. The cells cannot rid themselves of these proteins. In fact, we can see the cumulative toxicity when we examine the brain of a patient with AD who has passed away.

AD is caused by progressive brain cell death over time. We believe that AD, as well as other neurodegenerative disorders, can be treated by addressing breakdown in the cells’ autophagic pathways. If the pathways can return to functioning properly, the cells may able to engage in their own housekeeping and free themselves of the damaging detritus.

My team is looking at ways to clear the autophagic pathways in these cells. Because of advanced technologies, we can use chemical libraries to screen for and identify existing drug molecules that promote the proper function of these cleaning pathways.

With this generous grant, we have identified such molecules. We have also synthesized the molecules because in doing so we can improve their drug properties.

As we move forward, we’re continuing to develop this class of molecules as drug candidates to further understand, and possibly treat, AD. Our progress has brought us closer to our goal of bringing relief to individuals and families living with this difficult and progressive neurological disease.

Posted October 15, 2018