Research Interests and Current Projects

As a neuroscientist, I have been mainly interested in deciphering the early molecular events that contribute to the pathogenesis of various neurodevelopmental and neurodegenerative diseases. In particular, I am interested in determining how environment factors increase the risk of developing various neurodegenerative disorders, with a strong focus on Alzheimer’s Disease (AD).  Additionally, we aim to identify new therapeutic targets for discovery of drugs that can ameliorate disease progression.  Our lab uses a combination of postmortem human brain tissue in addition to various lines of animal models of Down Syndrome (DS) and AD to test our hypotheses. I strongly believe that in order to progress outcomes within research, collaborations are key. Sharing knowledge through publications, mentorship, teaching and public seminars have been key to furthering my scientific career. My ultimate goal is to make a large impact by both progressing science and consecutively helping those who suffer from insidious disease.   Current projects in the laboratory include: 

The Pim1 kinase as a contributor to the pathological progression of Alzheimer's disease
Pim1, a protein kinase from the proto-oncogene family, emerged in research as it is elevated in various cancers. Within the brain, Pim1 is expressed exclusively in the cortex and hippocampus, two brain regions that are highly vulnerable to AD pathology. We identified Pim1 as being dysregulated in post-mortem brain tissue of patients with early and late stages of AD compared to age-matched controls. Physiologically, Pim1 phosphorylates and regulates the activity of the proline-rich AKT substrate 40 kDa (PRAS40), which is involved in modulating protein degradation. Pim1 also plays key functions in long-term potentiation and synaptic plasticity, and increased Pim1 activity is linked to seizures and neuronal death. Pim1 is regulated by JAK/STAT, a pathway activated by inflammation. Our recent data illustrates that Pim1 is elevated in CA1 hippocampal neurons of AD patients and our published work shows that pharmacological inhibition of Pim1 rescues AD pathology in 3xTg-AD mice. Notably, 3xTg-AD mice develop amyloid-β plaques and pathological tau, which are the two hallmark pathologies in AD. The current goals of this project are to determine how modulating neuronal Pim1 activity interferes with AD pathology and to dissect the upstream mechanisms linked to Pim1 upregulation. We hypothesize that activation of the JAK/STAT pathway by inflammatory cytokines increases Pim1 activity, which in turn facilitates the development of AD pathology.  

Deciphering the early molecular events in Down syndrome that contribute to Alzheimer's Disease progression
Growing evidence indicates that Alzheimer's disease (AD) starts decades before its clinical manifestation. Early clinical interventions are needed to effectively mitigate the progression of AD. However, the initial triggers in the cascade of pathological events leading to AD remain elusive. Virtually 100% of people with DS will show brain accumulation of amyloid-β (Aβ) and tau in their fifth decade of life. Despite these data, little is known about the processes linking DS to AD. We postulate that dissecting the molecular mechanisms driving AD pathology in DS patients will lead to a better understanding of the etiology of AD. Previous work indicates that the mammalian target of rapamycin (mTOR) is hyperactive in human and animal models of DS and AD. Further, hyperactive mTOR signaling facilitates the accumulation of Aβ and tau. Together, these novel and exciting findings may answer a fundamental unresolved question: which event triggers the development of AD neuropathology in DS. The answer to this question will unveil mechanistic changes linked to the etiology of AD. The overall hypothesis of this project is that dysfunctional tuberous sclerosis complex 2 (TSC2), which is a regulator of mTOR, increases it’s activity in DS, which in turn contributes to the development of AD-like neurodegeneration. The results from this work will lead to a better understanding of the mechanism leading to neurodegeneration in DS and AD and will identify new therapeutic targets for these two disorders.

S6K1 as a novel link between aging and Alzheimer’s Disease 
Aging is the primary risk factor for AD and related disorders. Nevertheless, the mechanisms by which aging contributes to the onset of the disease remain elusive. In this project, we will attempt to identify critical signaling pathways that might link aging to AD pathogenesis. We focus on the ribosomal protein S6 kinase 1 (S6K1), a ubiquitously expressed protein with an established link to aging. Genetic deletion of the S6K1 gene in mice increases lifespan and decreases the incident of age- dependent motor dysfunction, insulin sensitivity, and obesity. A large body of evidence also points to S6K1 as playing a pivotal role in regulating astrocyte function during physiological and pathological conditions. For instance, reduction of S6K1 signaling reduces secretion of pro-inflammatory cytokines in activated astrocytes. It’s been shown that S6K1 activity is increased in postmortem human AD brains. In addition, genetic reduction of S6K1 ameliorates amyloid-β and tau pathology and improves synaptic function and cognition in 3xTg-AD mice, a widely used animal model of AD. For this project, we will identify the relative contribution of astrocytic and neuronal S6K1 hyperactivity in AD.  In addition, will identify the role of S6K1 in the gene expression dysregulation observed in AD. This project will define the mechanistic links between S6K1 and AD. Elucidating these mechanisms will likely identify several novel putative therapeutic targets for AD.

Glyphosate exposure a risk factor for cognitive aging and Alzheimer’s disease
Glyphosate is a toxic herbicide that has been the most heavily used since its inception in the 1970s. Glyphosate-based herbicides often contaminate drinking water, precipitation, and air in agricultural communities and products.  While the effects of glyphosate toxicity have been extensively studied in relation to the peripheral body, they have not in the brain. This fact is particularly concerning since glyphosate can cross the blood-brain barrier (BBB) in humans. Notably, correlations exist between AD and dementia death rates and glyphosate exposure. However, it has yet to be determined whether there is a causal relationship between glyphosate exposure and AD. Given that environmental factors are at play for late-onset sporadic AD, which accounts for >95% of those affected, understanding whether glyphosate exposure plays a role in inducing cognitive deficits could determine if glyphosate is, in fact, a risk factor for this insidious disease. The overall goal of this project is to identify the detectable level of glyphosate that induces cognitive deficits in humans and to determine whether such exposure increases AD risk and neuropathology.

Determine whether choline deficiency increases Alzheimer’s disease pathology. 
Choline is a B‐like vitamin nutrient found in common foods that is important in various cell functions. It serves as a methyl donor for epigenetic mechanisms and as a precursor for production of cell membranes. Choline is also the precursor for acetylcholine, a neurotransmitter which activates neurons important for various cognitive functions. Decades of work have shown that the current recommended daily intake amounts of choline established by the Institute of Medicine in 1998 may not be optimal for a graceful aging process. Even more concerning is that recent reports show only 15% of Americans are achieving the recommended daily intake amount of choline per day and the United Kingdom has no established recommendations. The goal of this project is to determine whether a deficiency in daily choline consumption increases the risk of developing AD and associated cognitive deficits.  

Techniques performed in our laboratory 

  • Development and usage of genetic mouse models of Down syndrome, Alzheimer's Disease and tauopathies (e.g. Ts65Dn, APP/PS1, PS19, APP Knock-in). 
  • Immunohistochemistry                                                                      
  • Western blot
  • Confocal Microscopy
  • MBF unbiased stereology and Neurolucida dendritic spine quantification
  • Genotyping and qPCR
  • Behavioral assessment in mice (Rota Rod, Morris water maze, Radial arm water maze)
  • Automated behavioral assessment in mice using the TSE IntelliCage system