Paramita Chakrabarty

Research topics

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

• Alzheimer's and Dementia
• Developmental Cognitive Neuroscience

Active NIH awards

• Deciphering tau phosphorylation and Abeta/tau strain interactions in Alzheimer’s pathogenesis

  5R01AG078734-04

  NIA · FY 2025 · $481K

  Abstract The clinical symptoms of Alzheimer disease (AD) dementia occur downstream of pathological deposition of Aβ peptides in extracellular cored-neuritic plaques and aggregated tau protein in intracellular neurofibrillary tangles (NFT) in the brain. Since deposition of Aβ precedes tauopathy in early-onset familial AD (fAD), it is accepted that Aβ can trigger tau misfolding into NFT, initiating a cascade of cumulative pathology that progressively leads to dementia. In sporadic AD, the coincident deposition of Aβ appears to correlate with tau misfolding and the severity of NFT pathology. Collectively, these findings suggest that Aβ deposition can exacerbate tau misfolding and NFT formation leading to cognitive deficits and dementia. However, the underlying mechanisms and characteristics of Aβ and tau that synergize resulting in NFT pathology and pathological sequelae is still unclear. Our proposal is designed to provide experimental insights into the individual contribution of tau (Aim 1) and Aβ (Aim 2) in driving Aβ-tau synergy in mouse models of AD. Evidence suggests that a major mechanism by which Aβ synergizes with tau misfolding involves the hyper-phosphorylation of tau. A recent study of AD patients that quantitatively mapped the progressive emergence of phosphorylated epitopes in tau identified 19 Ser/Thr residues that are most frequently phosphorylated in individuals that exhibit concurrent Aβ pathology. The main objective in Aim 1 is to dissect the contribution of these phosphorylation events in the misfolding and aggregation of tau that occurs in the presence of concurrent Aβ pathology. Using AAV technology, we have the capability to generate and express a large number of tau phospho-mimetic variants in APP TgCRND8 mice. Using this mouse model, in Aim 1 we propose a broad study to systematically dissect the phosphorylation events that drive tau misfolding and NFT formation in the presence of Aβ. Over many years of research, our laboratories have created mouse models that exhibit a spectrum of Aβ pathologies, including mice that develop primarily diffuse Aβ pathology and mice that primarily develop cored- neuritic pathology. Given that there are questions regarding the type of Aβ pathology that underlie Aβ-tau synergy, in Aim 2, we propose to use our AAV approach to examine Aβ-tau interactions in this diverse collection of APP transgenic models that exhibit different types of Aβ pathology. Additionally, in Aim 2, we will use pharmacologics and inducible APP models to examine the role of newly-made soluble Aβ vs long-lived insoluble Aβ in tau phosphorylation/aggregation process. Phospho-proteomic analysis will help us determine the relationship of different types of Aβ to the resulting tau phosphorylation profile. Collectively, this work will improve our understanding of the Aβ-driven phosphorylation cascade that appears to promote tau misfolding and aggregation into NFT.

• Modeling the progression of SOD1-linked motor neuron disease

  5R01NS092788-09

  NINDS · FY 2025 · $356K

  In the past 5 years, it has become clear that the protein pathology of many human neurodegenerative diseases exhibits characteristics of prions, including transmissibility, strain variation, and the ability to spread from a focal site of introduction. Amyotrophic lateral sclerosis (ALS) stands out as an example where the hallmarks of prion-like spreading is evident as weakness spreads along anatomically connected pathways. In familial ALS caused by mutations in superoxide dismutase 1 (SOD1-ALS), patients inheriting the A4V variant of SOD1 weakness spreads rapidly (average survival <1.5 years after the onset), whereas in patients inheriting the G37R variant weakness spreads slowly (average survival ~17 years). In the initial funding period of this award, our laboratory has uncovered evidence that this defining feature of SOD1-ALS may be explained by prion-like characteristics of mutant SOD1. Transgenic mice that express low levels of ALS mutant SOD1 develop disease late in life if at all. We have shown that paralysis can be accelerated in these mice by injecting spinal cord homogenates prepared from paralyzed mutant SOD1 transgenic mice or from human patients. We have also shown that we can inject these homogenates into the sciatic nerve of vulnerable mice to initiate a disease process that closely mimics the unilateral spread of weakness from one limb to another limb that is seen in humans. We have also successfully used purified recombinant SOD1 fibrilized in vitro to seed early onset paralysis in host mice, proving that SOD1 is capable of acting like a prion. Because we can propagate disease- causing conformations of SOD1 to naïve SOD1 “host proteins”, from hereafter we will refer to the misfolded conformation associated with disease-causing mutant SOD1 as an ALS prion. Building on the success of our initial work, we now propose four Specific Aims that are designed to improve our understanding of the biological role of prion-like spread in the pathogenesis of SOD1-ALS. In Aim 1, we seek to investigate whether the disease-causing mutations encrypt unique strain-like characteristics in misfolded SOD1 that influences the rate of prion-like spread in animal to animal transmission studies. In Aim 2, we seek to determine how the route of transmission and age of the host recipient mouse influence the propagation of SOD1-ALS prions. In our third and fourth Aims, using our novel model system we will turn our attention towards determining the extrinsic factors that determine how misfolded protein conformations may spread in the CNS and whether inflammatory signaling may influence such spread. In Aim 3, we will use newly generated loxp G85R-SOD1:YFP mice to determine the contribution of astrocytes in propagating SOD1-ALS prions. In Aim 4, we will use adeno- associated vectors to express pro- and anti-inflammatory cytokines as a means to assess the role of activated astrocytes and microglia in the propagation and spreading of SOD1-ALS prions. Our over-arching goal is to determine the contribution of intrinsic strain-like attributes in SOD1 and extrinsic non-cell autonomous processes to the prion-like propagation properties of disease-causing SOD1 conformations.