Diego E Rincon-Limas

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Alzheimer's and Dementia
• Learning and Memory
• Cognitive Aging
• Developmental Cognitive Neuroscience

Active NIH awards

• Can SARS-CoV-2 proteins accelerate Abeta pathology in fly and mouse models of AD?

  1R21AG091384-01

  NIA · FY 2025 · $419K

  The onset of the COVID-19 epidemic in December 2019, caused by the novel SARS-CoV-2 coronavirus, unleashed a catastrophic toll, claiming over 7 million lives and imposing an unparalleled strain over the healthcare, social, and financial systems worldwide. Although COVID-19 is no longer a global emergency, the healthcare burden continues. This is because thousands of people have experienced multiple neurological symptoms for months or even years after the initial infection, which is referred to as Long Covid. These symptoms include “brain fog”, persistent headache, disturbed consciousness, fatigue, and cognitive decline to name a few. Unfortunately, hardly anything is known about the molecular underpinnings of these prolonged neurological manifestations and the potential involvement of SARS-Co-V2 proteins in the onset of degenerative dementias like Alzheimer’s disease (AD). To address this gap, we screened all 29 proteins encoded by the SARS-CoV-2 genome and found one non-structural protein that induces a very aggressive phenotype when expressed in the eye of transgenic flies as well as loss of axonal projections when expressed in the Drosophila brain mushroom body neurons, which are associated with memory functions. Strikingly, we also found that this protein aggravates Abeta42-dependent neurodegeneration and dramatically exacerbates Abeta42 aggregation as evidenced by thioflavin staining. This suggests that the potential presence of this SARS-CoV-2 protein in the brain could trigger a response to influence the development of Alzheimer’s disease. To test this hypothesis, we will perform an age-dependent study of the neurotoxic role of this protein in a Drosophila model of Abeta42 deposition using genetic, molecular and behavioral approaches (Aim1) as well as a comprehensive pathological analysis in mouse models of Alzheimer’s disease (Aim2). This complementary work in flies and mice is highly significant because it may uncover a groundbreaking pathological association between coronavirus proteins and Alzheimer’s disease. In addition, it may also lead to a paradigm shift to guide new research priorities to prevent a potentially devastating public health crisis in the future.

• Harnessing new targets and mechanisms mediating AD pathogenesis

  5R01AG077534-03

  NIA · FY 2025 · $374K

  Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss and cognitive decline, and is the No.1 cause of dementia. It is characterized by the coexistence of extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis, which significantly hinders the development of effective treatments. To address this, we generated a new fly model of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display extracellular deposits of thioflavin-S-positive Abeta, intracellular aggregation and phosphorylation of wild-type tau, and progressive loss of neuronal cells. The robust and consistent pathology of these flies provides a unique opportunity for gene discovery efforts and thus we performed a massive loss-of-function RNAi screen in the fly eye, which provides a useful and easy-to-score phenotype. Out of 6,600 RNAi stocks tested, we identified 31 suppressors and 119 enhancers, including multiple genes not previously known to be associated with AD. Most suppressors are linked to protein modification or cleavage, ribosomal function, cell metabolism, transcription, chromatin modulation, and transport to name a few. Here, we will employ a strategically designed pipeline that integrates genetics with high-throughput behavioral platforms and target prioritization to identify robust late-stage modifiers of the disease (Aim 1). On the other hand, we will fast-track a mechanistic and therapeutic analysis of one of the strongest suppressors along with its human homologue (Aim 2). This suppressor encodes a highly disordered protein of uncharacterized function and was also found in two other genetic screens performed by us. Thus, we have labelled it as a high-priority target. We strongly believe that manipulation of the 150 modifiers of Abeta+tau toxicity presented here will provide the foundation for new types of targets or therapeutics. Therefore, this work may contribute significantly to the goals of the National Plan to Address Alzheimer’s Disease.