Research Findings

Research Results

According to the rules outlined in each grant awarded by The CART Fund, researchers are required to submit regular progress reports on their work. We are pleased to provide the final updates from previous CART Fund grant recipients outlining the results of their research. Please note out of respect for their intellectual and proprietary material, we will only publish final reports rather than the progress reports that have been submitted.

If you have an interest in a particular ongoing research project, please do not hesitate to contact us for additional information.

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.

“We are so grateful for the support of CART and the Rotarians,” says Jerold Chun, M.D., Ph. D. of Sanford Burnham Prebys. “They’ve shown over the years that small contributions to Alzheimer’s research can add up to make a huge impact.”

You can read more about Dr. Chun's 2022 grant here.

Dr. Levi Wood (Georgia Institute of Technology)

Dr. Levi Wood was the recipient of a $187,500 grant from The CART Fund in 2019. 

Alzheimer’s disease afflicts the health of neurons and the ability of the immune system to clear plaques from the brain. Thus, successful treatment strategies will be needed to simultaneously treat both the neurons and the brain’s immune system. Researchers at Georgia Tech have come up with an idea to address both of these needs simultaneously and non-invasively. Their treatment approach consists of non-invasively exposing the eyes and ears to flickering lights and sounds to stimulate distinct groups of genes that promote neuronal health or the brain’s immune system. In the current study, the investigators are building a map of the genes stimulated by different frequencies and durations of stimulation.

To do so, the investigators have exposed more than 100 healthy and Alzheimer’s mice to audio/visual flicker and measured approximately 20,000 genes in each of their brains in response to different frequencies of flicker for durations from 30min-4hr. The team has discovered that each of these treatments yields different effects on genes involved in neuron health and brain immunity. They have found that multiple frequencies can stimulate genes promoting neural function, whereas different frequencies (20 vs 40Hz) have distinct effects on immune genes.

These findings suggest there may be optimal treatment strategies that promote both healthy neuron and immune function. The investigators are currently revising their analysis for publication. They envision that their stimulation-to-gene expression map will form the foundation of a transformative new way to treat Alzheimer’s disease.

Dr. Mark Albers (Massachusetts Institute of Degenerative Disease)

Dr. Mark Albers was the recipient of a $187,500 grant from The CART Fund in 2019. 
Alzheimer’s disease is growing at alarming rates as our population ages; yet there are no disease modifying therapies available to date. Repositioning FDA approved drugs offers an accelerated path to test drugs in AD patients since the safety profile for these drugs has been established.  We and others have documented activation of innate inflammation in autopsied brains of patients with Alzheimer’s disease (AD), but the triggers of inflammation remain elusive.

Recently, we discovered a root cause of inflammation in about half of AD patients. A certain class of FDA-approved drugs for inflammatory disorders may interfere with this type of brain inflammation. Based on these exciting results, CART funding is helping us to shed further light on the connections between this inflammatory trigger in the brain cells of patients with AD and the complex inflammatory responses in these brains. Through this work, we are gaining a better understanding of how neurons die in response to this inflammation.

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Dr. Michael Kahn (Beckman Research Institute, City of Hope)

Dr. Michael Kahn was the recipient of a $187,500 grant from The CART Fund in 2019. 

Adult stem cells (ASC) live with us our entire lives and are responsible for the maintenance and repair of our bodies. With aging, there is a significant deterioration in the function of ASC, leading to reduced and/or defective ability for maintenance and repair. For the past 20 years, the Kahn Lab research focus has been to investigate the potential to pharmacologically manipulate our ASC populations to “rejuvenate” them.

The brain’s ability to adapt and reorganize itself by forming new connections is maintained throughout our life. Brain stem cells are a type of ASC which reside in the hippocampus, a region of the brain that is critical in memory formation and also in initiating repair processes in response to insult and injury.



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Dr. Carl Wagner (Arizona State University)

Dr. Carl Wagner was the recipient of a $112,500 grant from The CART Fund in 2018. 
Researchers at ASU continue to make progress in the synthesis and evaluation of new experimental therapeutics targeting a critical protein that impacts Alzheimer’s—apolipoprotein E (apoE)—through a Coins for Alzheimer’s Research Trust (CART) Fund grant.  The researchers have recently identified three new drug-like molecules that activate a receptor involved in the synthesis of apoE in human neuronal cells, and they are currently examining whether the apoE protein is produced in greater quantities in the cells treated with these compounds than in untreated cells.  The apoE protein is responsible for helping to remove from the brain a substance called amyloid-beta—a protein that is frequently found in plaques in Alzheimer’s patient brains.  Identifying new drug compounds that lead to greater levels of functional apoE in human brain cell lines may lead to new Alzheimer’s therapeutics that can reduce levels of amyloid-beta in Alzheimer’s patients.

Dr. Keith Vossel (University of Minnesota)

Dr. Keith Vossel was the recipient of a $112,500 grant from The CART Fund in 2018. 

People with Alzheimer’s disease often experience seizures and silent seizure activity in the brain, accelerating the memory loss associated with the disease. We know that the tau protein in brain cells is linked to seizures and memory loss in patients with Alzheimer’s, but we do not know exactly how tau contributes to these seizures and ultimately causes cell death in the brain.

With support from The CART Fund, Dr. Vossel’s team has discovered new mechanisms by which tau contributes to epilepsy and memory loss in Alzheimer’s disease. Dr. Vossel’s team has found that by creating modifications in tau’s structure, they can prevent seizures and cell death that occur in Alzheimer’s disease models. They have used advanced molecular imaging to determine that the modifications prevent tau from attaching to molecules that are implicated in both epilepsy and Alzheimer’s disease.

 



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Dr. Nicola Allen (Salk Institute)

Dr. Nicola Allen was the recipient of a $112,500 grant from The CART Fund in 2018.

In their research, the Allen lab has shown that the star-shaped support cells called astrocytes regulate neuronal function throughout life. In the young brain, astrocytes initiate and maintain connections between neurons, while in the aging brain astrocytes may contribute to the loss of neuronal connections and function. Given this close relationship between the two types of brain cells, astrocytes are likely central to development of Alzheimer’s disease (AD).AD is characterized by the loss of neuronal connections, known as synapses, which leads to cognitive decline.

The Allen lab aims to better understand the role of astrocytes in AD and test whether targeting astrocytes can be used as a therapy to slow or reverse the loss of synapses. In their CART project, the researchers have used AD mouse models to analyze gene expression in astrocytes to understand the specific changes to astrocytes that accompany synapse loss.
 



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Dr. Claudio Torres (Drexel University)

Dr. Claudio Torres was the recipient of a $50,000 grant from The CART Fund in 2017.
Research funded by the Coins for Alzheimer’s Research Trust (CART), a project of the Rotary Clubs of North America, has shown further correlation between cellular aging, or senescence, and Alzheimer’s disease (AD) pathology. The group of Dr. Claudio Torres at Drexel University in Philadelphia, PA analyzed cellular senescence in different cell types in brain regions affected or not affected by AD using post-mortem brain tissue from AD patients and use of antibodies specific to senescence markers to visualize these cells under the microscope.

Cellular senescence occurs with age, and results in cells being unable to divide and replenish their population, and also losing some function and being pro-inflammatory. Torres’ group showed that a marker of unresolved DNA damage that is typically used as a marker of senescence, was increased in glia, or helper cells, in a brain region (temporal cortex) affected in intermediate stage of AD, while in another region, the cerebellum, which is not affected by disease, there was no increase in senescence either.

 



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Dr. Tong Li (Johns Hopkins University)

Dr. Tong Li was the recipient of a $75,000 grant from The CART Fund in 2017.
Age is the most important risk factor for development of Alzheimer’s disease (AD). How aging increase the chance for people to develop AD is still unclear. To address this critical question, we proposed to use a newly developed mouse model of AD to test whether aging could facilitate the development of a protein aggregation called the tau tangle, which is a key hallmark in the brain of AD patients. We found that when mice were allowed to start accumulation of tau aggregation at 6 month or 12 month of age (mimicking young adult and middle age in humans), the onset and development of tau pathology were not changed.

However, when tau accumulation in mice were started at 16 month of age (mimicking advanced age in humans), much more severe tau aggregation, neuron cell loss and brain atrophy were observed. These results demonstrated that aging accelerated development of tau aggregations. In addition, we also found that age also play an essential role in the sex differences in AD. Our studies demonstrate that the age could increase the risk of AD by accelerating the development of tau aggregation. Understanding the aging related mechanism in AD will provide new strategies for designing effective treatments for AD.

Dr. Tsuneya Izeku (Boston University)

Dr. Tsuneya Izeku was the recipient of $100,000 grant from The CART Fund in 2017.

We have completed the assessment of selected drugs for targeting an enzyme tau-tubulin kinase 1 (TTBK1) by biochemistry, toxicity to cells, toxicity to animals and efficacy of inhibiting the toxic modification of tau protein in animal brain.  After assessment of these data, it was determined that none of the selected drugs are good enough for next step. We performed second screening of modified drugs from the original best candidate drug, but none of them show inhibition activation against target enzyme.

New drug candidates are found based on the screening software for simulation of drug-enzyme interaction. We plan to test those new candidates for its inhibition activity against target enzyme as a backup strategy in the future.

Dr. Michael Karin (University of California San Diego School of Medicine)

Dr. Michael Karin was the recipient of $150,000 grant from The CART Fund in 2017.

The foundation of our work is the proposal that chronic neuronal inflammation (i.e neuroinflammation) plays a key role in the progression of Alzheimer’s Disease and other types of late onset neurodegenerative diseases. While inflammation is usually associated with pain, fever and swelling, there is evidence that it also plays an important role in neurodegeneration.

Accordingly, we hypothesize that damage to the brain’s neurons due to aging and/or trauma results in the release of normal cellular components, such as the energy storing molecule ATP, that can evoke an inflammatory response when encountered by specialized immune cells that reside in the brain called microglia.

 



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Dr. Philip Copenhaver (Oregon Health & Science University)

Dr. Philip Copenhaver was the recipient of a $75,000 grant from The CART Fund in 2017. 

“A Novel Modulator of membrane estrogen receptors for treating AD”

During Alzheimer’s Disease, toxic amyloid proteins accumulated in the brain of patients, but clinical trials designed to reduce amyloid have failed.  As an alternative strategy, we have tested a promising compound called STX that might protect patients by supporting the overall health of brain cells.  STX was originally developed as a replacement for estrogen (the female sex hormone).

With support from The CART Fund, we have explored the protective mechanisms of STX. We found that STX activates an important signaling cascade inside nerve cells (called “PI3K” signaling), which stimulates protective responses in other diseases.

Like estrogen, STX can prevent the loss of brain cells in an animal model of stroke.  However, STX does not cause the side effects of estrogen that can harm AD patients, suggesting that it can be used to treat both men and women. In early studies, we discovered that STX protected isolated nerve cells against toxic amyloid, in part by improving the production of cellular energy in the brain. 
 



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Dr. Christelle Anaclet (University of Massachusetts Medical School)

Dr. Christelle Anaclet was the recipient of a $250,000 grant from The CART Fund in 2017. 

The goal of our work is to develop new mouse models to test the role of sleep in memory, both in healthy individuals and in Alzheimer’s Disease models. Alzheimer’s Disease is associated with both sleep impairment and memory deficit. Two major sleep stages are distinguished, slow-wave-sleep (SWS) and rapid eye movement sleep (REMS).

Historically, loss-of-sleep experiments have suggested a beneficial role of SWS in declarative memory and a beneficial role of REMS in non-declarative memory, but these experiments have been unable to describe what it is about sleep that might enhance these functions.



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Dr. Chihiro Sato (Washington University School of Medicine)

Dr. Chihiro Sato was the recipient of a $125,000 grant from The CART Fund in 2016. 

Thanks to the generous support from CART, Drs. Sato and Barthelemy published multiple papers describing distinct tau profiles in the human brain, cerebrospinal fluid, and neurons in a dish. Dr. Barthelemy also found that the phosphorylation ratio at position T217 on the tau protein serves as a more sensitive AD biomarker compared to the commonly used T181.

In their research supported by CART, they developed methods to measure tau, phosphorylated tau (p-tau) and specific isoforms that result from alternative splicing and truncations in the human brain, CSF and cell culture models. They used tau antibodies to capture and concentrate tau proteins in the sample, then used mass spectrometry methods to describe and measure which types of tau (splicing variants, truncations, chemical modifications such as phosphorylation) are present in the brain, CSF and neurons in cell culture.

 



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Dr. Thomas Anastasio (University of Illinois)

Dr. Thomas Anastasio was the recipient of a $50,000 grant from The CART Fund in 2016.

Alzheimer Disease (AD) remains the leading neurological killer, and “the amyloid hypothesis” remains the leading theory of AD. “Amyloid-beta” is the abnormal protein fragment that accumulates in AD brains and that composes the “amyloid plaques” that are found in AD brains.  The amyloid hypothesis says that amyloid-beta causes AD – but it’s wrong! Treatment strategies aimed at reducing amyloid-beta don’t work!

These and other observations show that amyloid-beta is not the only factor that underlies AD. Instead, research shows that AD is “multifactorial” in that it is caused by many different factors, not just amyloid-beta. And because AD is multifactorial, it probably should be treated with combination therapies that target multiple factors. But this poses a problem because the design of combination therapies to treat multifactorial diseases is highly complex. One project funded by the CART foundation addressed this problem.

 



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Dr. Frank Sharp (University of California at Davis)

Dr. Frank Sharp was the recipient of a $125,000 grant from The CART Fund in 2016.

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.
 

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Dr. Yueming Li (Memorial Sloan Kettering Cancer Center, NYC)

Dr. Yueming Li was the recipient of a $250,000 grant from The CART Fund in 2016.

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.

 



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Dr. Wenjie Luo (Cornell University)

Dr. Wenjie Luo was the recipient of a $100,000 grant from The CART Fund in 2015.

Investigating the role of microglia in tau clearance in Alzheimer’s Disease

During these three years supported by the CART Fund, we have performed the experiments as proposed in the original plan and obtained extensive knowledge about how microglia degrade pathological tau based on the following scientific results. In our original proposal, we planned to investigate the mechanism how brain phagocytic cell microglia play a role in the brain clearance of tau, a pathologic protein that can spread from neuron to neuron and form deadly neurofibrillary tangles in Alzheimer’s Disease (AD).
 



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