Foundation Award Recipients

Foundation awards are distributed each year on April 16th and August 30th.

30-August-2018 recipient:

Drexel University
(Neuroscience Research)

Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, its misregulation may contribute to cognitive impairment preceding Alzheimers Disease (AD) pathology.
In their May 2018 publication, Panikker, et al. suggest that disruption of the Tip60 HAT/HDAC2 balance is a critical initial step in AD. They report that this disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the AD Drosophila brain and triggers epigenetic repression of neuroplasticity genes before A-beta plaques form. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition.
In recognition of the Elefant Lab's important insights into the mechanism of epigenetic transcriptional repression in the neurodegenerative brain, we have selected Drexel University (Neuroscience Research) as our August 30th, 2018 funding recipient.

16-April-2018 recipient:

University of Texas Southwestern Medical Center
(Neuroscience Research)

Studies suggest that dendritic spine loss, a characteristic of early Alzheimers disease (AD), is induced by soluble, multimeric amyloid-Beta 42 (AB-42), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. An earlier retrospective study showed that human transplant patients receiving FK506, an inhibitor of calcineurin, developed AD at a much lower incidence than expected. But since a calcineurin inhibitor such as FK506 can produce serious immunosuppressant and carcinogenic side effects, a more complete understanding of molecular mechanisms will be necessary to identify more specific targets for more precisely targeted drugs.
In their March 2018 publication, Stallings, et al. report that Pin1 is a critical downstream dephosphorylation target of AB-42-calcineurin signaling. The researchers report that knockout of Pin1 or exposure to AB-42 induced the loss of mature dendritic spines, but that that spine loss could be prevented by the addition of exogenous Pin1. Interestingly the calcineurin inhibitor FK506 blocked dendritic spine loss in AB-42-treated wild-type cells but had no effect on Pin1-null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer’s disease.
In recognition of the Malter Lab's important insights into the mechanism of calcineurin inhibitors in resistance to AD-related neurodegeneration, we have selected University of Texas Southwestern Medical Center (Neuroscience Research) as our April 16th, 2018 funding recipient.


30-August-2017 recipient:

Weill Cornell Medicine
(Neuroscience Research)

The CACNA1C gene, encoding the Cav1.2 subunit of L-type calcium channels, has emerged as a candidate susceptibility gene for multiple neuropsychiatric disorders including bipolar disorder, schizophrenia, major depressive disorder, and autism spectrum disorder. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical structure and activity.
In their August 2017 publication, Kabir, et al. report that knock-out mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) and adult mice with focal knockdown of cacna1c exhibit anxiety-like behavior and display a social behavioral deficit. But systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2-alpha on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in the adult cacna1c fbKO mice.
In recognition of the Rajadhyaksha lab's identification of a novel mechanism and potential future therapeutic target for anxiety and other neuropsychiatric-related behaviors we have selected Weill Cornell Medicine (Neuroscience Research) as our August 30, 2017 funding recipient.

16-April-2017 recipient:

Washington University in St Louis
(Neuroscience Research)

Because the accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer's disease, a promising therapeutic strategy may be to reduce total tau expression. Researchers from the Miller Lab at Washington University in St Louis have identified anti-sense oligonucleotides (ASOs) that selectively decrease human tau mRNA and protein in mice engineered to express mutant P301S human tau.
In their January 2017 publication, DeVos, et al. report that "After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed."
While showing beneficial effects at the molecular, cellular, anatomical, and behavioral levels in the mouse model, DeVos, et al. also showed that their tau-targeted ASOs reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid of non-human primates (cynomolgus monkeys).
In recognition of these important insights into the therapeutic possibilities of tau reduction in both mouse and primate models we have selected Washington University in St Louis School of Medicine (Neuroscience Research) as our April 16th, 2017 funding recipient.


30-August-2016 recipient:

Salk Institute for Biological Studies
(Neuroscience Research)

Although beta-amyloid (A-beta) has been associated with Alzheimers Disease since the initial characterization of the disease, the mechanistic relationship between intracellular amyloid, aging, and neurodegeneration is not well understood. Using a human central nervous system cell line that conditionally expresses A-beta, researchers from the Schubert lab at the Salk Institute have characterized a distinct form of nerve cell death caused by intracellular A-beta in which A-beta induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids.
Through identifying the molecular basis of this inflammatory response Currais, et al. (23-June-2016) demonstrate that intracellular A-beta accumulation and this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors, with tetrahydrocannabinol showing a particularly potent protective effect.
In recognition of these important insights into the inflammatory pathways associated with Alzheimers Disease pathology and possible therapeutic approaches we have selected The Salk Institute for Biological Studies (Neuroscience Research) as our August 30th, 2016 funding recipient.

16-April-2016 recipient:

Johns Hopkins University School of Medicine
(Neuroscience Research)

A major limitation of current antidepressant drug therapy is the lag of weeks to months before attaining any therapeutic benefit. Moreover, a significant percentage of depression patients experience no benefit from these drugs after any period of time.
Ketamine has been shown to relieve clinical depressive symptoms in as little as 2 hours with therapeutic effects lasting for a period of weeks, even in otherwise drug resistant cases of depression. However ketamine, an anesthetic, can produce serious side effects including hallucinations, dissociative dream-like state, and possibly addiction. Producing a new generation of antidepressant drugs that deliver ketamine's rapid and long-acting effects while minimizing side effects and potential for abuse will require a detailed understanding of its molecular mechanism of action.
In March 2016 Harraz, et al. of Johns Hopkins University published a report in which they used biochemical, neuronal cell culture, and mouse behavioral studies to describe a novel signaling pathway in which ketamine stabilizes a small G protein, Rheb, which activates mTOR to exert antidepressant actions. In recognition of their efforts to begin to describe the molecular mechanisms involved in the rapid and lasting antidepressant effects of ketamine, we have selected Johns Hopkins University School of Medicine (Neuroscience Research) as our April 16th, 2016 funding recipient.


30-August-2015 recipient:

University of Kentucky College of Medicine
(Neuroscience Research)

Researchers at the University of Kentucky published results last month describing a connection between memory impairment and declining levels of a naturally occurring protein involved in immune response and calcium regulation in neurons, called FK506 Binding Protein. This UK study follows a June 2015 University of Texas Medical Branch publication showing, for the first time in humans, almost complete protective effects against the development of dementia in organ transplant recipients who have been receiving calcium-regulating immunosuppressant drugs such as FK506. In support of their continued efforts to discover the molecular mechanisms involved in neuronal calcium regulation and its connection to age and disease-related memory loss, we have selected the University of Kentucky College of Medicine (Neuroscience Research) as our August 30th 2015 funding recipient.
continued...
Animal models in neuroscience research have long been indispensable in deciphering cellular mechanisms of the Central Nervous System and how those mechanisms are altered by disease. In recent years studies on mice and rats (treated or genetically engineered to develop the same kinds of cellular, cognitive, and behavioral problems as seen in Alzheimerís Disease) have produced a model which ties the neurodegeneration and cognitive decline associated with Alzheimerís Disease (AD) to an overabundance of intracellular calcium. In this model, this imbalance in neuronal calcium induces multiple cellular changes including the hyperactivation of an abundant cellular protein called Calcineurin which, in turn, activates other proteins and sets in motion a cascade of reactions that ultimately account for the synapse loss, memory impairment, and other symptoms associated with dementia.
With Calcineurin playing a central role in the calcium-focused model, researchers have found that treating AD mice with an inhibitor of Calcineurin's ability to activate other proteins slowed, prevented, and even reversed synapse loss and memory impairment, lending support to the model. These reports, as interesting and encouraging as they may be, represent only a few of the many times that Alzheimerís disease has seemingly been cured in rodents. Transferring these successes to human patients, however, has yielded little clinical success.
But in June 2015 Luca Cicalese and colleagues at the University of Texas Medical Branch (UTMB) published data from humans that appears to give strong support to the proposed Calcineurin-dependent animal model. It turns out that Calcineurin-inhibitors such as FK506 and Cyclosporin-A have been used for decades in organ transplant recipients as anti-rejection immunosuppressant drugs. The UTMB group compared the prevalence of clinically diagnosed dementia in 2644 transplant patients who have been taking Calcineurin-inhibitors with that seen in the general public. While prevalence numbers in the youngest group (<65 years old) were both very low, the impact of the Calcineurin-inhibitor treatment was dramatically apparent in older groups.
    For people <65, dementia is diagnosed in 0.07% of the general population and 0.09% of the Calcineurin-inhibitor treated group(n=2/2057).
    For people >65, dementia is diagnosed in 11% of the general population but only 1.02% of the Calcineurin-inhibitor treated group (n=6/587).
    For people >75, dementia is diagnosed in 15.3% of the general population but only 0.6% of the Calcineurin-inhibitor treated group (n=1/149).
    And in the >85 age cohort, dementia is diagnosed in 32% of the general population but was undetected in the Calcineurin-inhibitor treated group (n=0/14).
That actual human disease prevalence data gives such strong support to the animal-based disease model marks an important milestone in Alzheimerís disease research, but the work is far from finished. The Calcineurin-inhibitor immunosuppressant drugs, such as FK506, that seemingly so effectively prevent the development of dementia in humans have serious side effects, including increased risk of infection and malignancies. For thousands of organ transplant recipients these risks are justified, but they would not be so for the general population. Rather, the calcium regulation model will need to be better understood so that more targeted drugs or other therapies that prevent neurodegeneration and memory loss while avoiding the immunosuppressive and carcinogenic side effects can be identified.
John Gant and colleagues at the University of Kentucky (UK) have provided a powerful example of further exploring the model with their 29-July-2015 publication describing a reversal of calcium imbalance and memory impairment in aging rats by overespressing (through genetic engineering) FKBP1b (FK506 Binding Protein), a protein that naturally declines with age and in Alzheimer's Disease patients. FKBP1b stabilizes intracellular calcium levels and binds to and mediates the activity of the Calcineurin-inhibitor FK506, one of the immunosupressant drugs in the UTMB study. The UK study's Principal Investigator, Philip Landfield, described the work as showing "...FKBP1b is a master regulator of calcium in brain cells, and when we restore it, it restores the regulation of calcium and dramatically improves learning in the aged animals."
To encourage such continued research in revealing the key molecules and pathways involved in the memory impairment and neurodegeneration observed in Alzheimer's Disease, we have chosen to support neuroscience research at the University of Kentucky College of Medicine through our 30-August-2015 research funding.



16-April-2015 recipients:

University of Louisville Depression Center

-targeting their projects in Cortical Mechanisms of Depression and Cognitive Neuroscience Research in Mood Disorders

UCI - MIND (Alzheimers Disease Excellence Fund)

-funding pilot research projects for junior investigators to develop preliminary data in the preparation of a formal NIH grant application.