Casey N Cook

Research topics

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

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

Active NIH awards

• Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells

  7R01AG071513-04

  NIA · FY 2024 · $631K

  PROJECT SUMMARY/ABSTRACT As the most common cause of dementia, Alzheimer’s disease (AD) is pathologically defined by amyloid beta (Aβ) deposition in senile plaques and tau aggregation in neurofibrillary tangles (NFTs). In addition to amyloidosis and tauopathy, demyelination is also a consistent, yet often overlooked, feature of AD. Notably, myelin loss is detected even at early stages of disease with decreases observed in patients with mild cognitive impairment (MCI). This implicates that dysregulation of the oligodendrocyte cell population, the brain’s myelin- producing cells, may be a critical factor in AD pathophysiology. Several recent studies from multiple groups consistently identified transcriptional alterations in myelination networks as a key feature of AD, underscoring the great need to elucidate disease-related alterations in the oligodendrocyte population to provide novel insights into AD pathophysiology. Of particular relevance, tau accumulation is associated with loss of white matter integrity in both human patients and mouse models of tauopathy. White matter abnormalities have even been detected in cognitively-normal carriers of the apolipoprotein E ε4 (APOE ε4) genotype, a population at high risk of developing AD. Given that ApoE4 has been shown to potentiate tau toxicity and ischemia-induced white matter damage in mice, these findings may indicate that tau burden and ApoE4 converge to drive white matter abnormalities in AD. Considering that oligodendrocyte progenitor cells (OPCs) respond to white matter damage by migrating to the site of injury and differentiating into myelinating oligodendrocytes to repair the lesion, a key question is why OPCs and/or oligodendrocytes fail to correct white matter abnormalities in the presence of abnormal forms of tau and/or ApoE4. A recent study found that OPCs in both postmortem brain and a mouse model of AD exhibited markers of cellular senescence, with pharmacologic removal of senescent OPCs alleviating inflammation and cognitive defects in mice. These results provide compelling evidence that OPC dysfunction may actually contribute to and exacerbate disease progression in AD. As such, the current study will investigate the impact of tau pathology and APOE genotype on abnormalities in OPCs and oligodendrocytes, including remyelination ability. In addition, given that deletion of the ApoE receptor, Lrp1, from OPCs provided neuroprotection, stimulated myelin repair and reduced inflammation in mouse models of demyelination, we will evaluate the protective effect of Lrp1 deficiency in OPCs in the context of tauopathy, as well as the role in exacerbation of tauopathy in the presence of ApoE4. Collectively, the current project will identify key functional and transcriptional alterations observed in the OPC/oligodendrocyte population in response to tauopathy and ApoE4, and determine whether loss of Lrp1 in OPCs mitigates ApoE4-mediated exacerbation of tau pathology.

• Impact of T cells on the CNS during aging and Alzheimer's disease

  7R01AG065219-06

  NIA · FY 2024 · $485K

  PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disease that results in amyloid β plaque deposition, neurofibrillary tangle (NFT) formation, and life-altering cognitive defects. Many human genetic AD risk factors, including APOE, CLU, and TREM2, modulate neuroinflammation and/or the function of microglia, the central nervous system (CNS) resident innate immune cell. Deletion of all peripheral adaptive immune cells (i.e. CD4+ T cells, CD8+ T cells and B cells) or T cell depletion (i.e. CD4+T cells, CD8+T cells) increased cognitive abilities in amyloidosis and tauopathy models, respectively, and were associated with altered microglial function. Interestingly, aging, another major AD risk factor, is associated with inflammation and we have found that increases in CNS CD8+ T cells found with aging is further exacerbated by amyloidosis. Additionally, enhanced CNS CD8+ T cells numbers are also found during tauopathy. We hypothesize that CD8+ T cells impact cognition and CNS sequelae during tauopathy and age-associated amyloidosis. We predict that CD8+ T cells alter microglia function and transcriptomes as a mechanism for disease modulation. To address this hypothesis, we will utilize aged wild type (WT) control mice, aged APPNL-F/NL-F mice, which express human amyloid precursor protein (APP) or our AAV1 model of tauopathy, respectively, on a normal WT or CD8-/- background, to eliminate CD8+ T cells. We will also conduct similar studies on an OT-I background which contains CD8+ T cells that are not stimulated through their T cell receptor (TCR). We will assess multiple parameters including behavioral/ cognitive performance (using open field assay, elevated plus maze, contextual fear conditioning and morris water maze), immunofluorescence/immunohistology examining plaque deposition, tau phosphorylation, CD8+ T cell localization and microglial/ astrocyte reactivity, flow cytometric analysis of CNS CD8+ T cell function, western blot analysis for total and phosphorylated tau, ex vivo microglial cultures and RT-qPCR to examine cortical and hippocampal gene expression of proinflammatory and anti-inflammatory factors. Furthermore, we will be using single cell transcriptomics to examine the entire RNA transcriptome on a per cell basis to assess CNS CD8+T cell transcriptomes and the impact of CD8+T cells on microglial transcriptomes and subpopulations during normal aging, age-associated amyloidosis or tauopathy. Our proposed work will be the first to define the transcriptomes of CNS CD8+ T cells in the context of age-associated amyloidosis or tauopathy. Additionally, we will address for the first time how CD8+T cells impact behavior/cognition, neuroinflammation, gliosis, microglial transcriptomes and pathology during age-associated amyloidosis or tauopathy. This work will provide highly novel insights into how peripheral and central immunity interact during aging and disease, and could provide the impetus to examine new therapeutic measures for management/alleviation of AD associated CNS sequelae.

• Mechanistic insights into the link between the A152T risk variant and tauopathy

  7R01AG063780-06

  NIA · FY 2024 · $386K

  PROJECT SUMMARY/ABSTRACT Pathogenic mutations in the tau gene (MAPT) are linked to the onset of tauopathy, but the A152T mutation is unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). As an unconventional approach to investigate the role of tau in neurodegeneration, we reasoned that understanding how the A152T variant modulates risk of AD and related disorders could reveal a common disease mechanism(s), uncovering novel strategies to increase resilience to tau toxicity and modify disease phenotypes in patients. Given the introduction of a new potential phosphoepitope, we questioned whether the A152T variant might impact disease risk through altered phosphorylation of tau on either T152 or the neighboring T153 residue. A series of novel antibodies were generated to test this idea, which revealed significant accumulation of soluble tau species hyperphosphorylated on T153 (pT153) in postmortem brain tissue from A152T carriers compared to noncarriers, as well as in mice expressing A152T-AAV. Therefore the current project will investigate the overall hypothesis that the A152T variant modulates disease risk through enhanced accumulation and increased solubility of pT153-positive tau, which subsequently primes tau for downstream pathological phosphorylation events and is critical for tau-mediated toxicity. Of note, phosphorylation on T153 and tau’s other serine/threonine-proline motifs has been shown to be required for tau toxicity, although the extent to which pT153 contributes to tau toxicity remains untested. In elucidating the pattern of pT153 deposition throughout the brain in A152T carriers and noncarriers, the proposed studies will determine if pT153-positivity coincides with neurodegeneration. Using site-directed mutagenesis and somatic brain transgenesis, we will determine whether pT153 is required for tau toxicity in vivo. Finally, incorporating rapidly evolving technology that is enabling acquisition of global gene expression profiles at the single cell level, we will assess whether expression of the A152T variant differentially impacts the transcriptome of individual cell populations. We anticipate that in uncovering the mechanisms by which A152T influences risk of tauopathy, and deciphering the involvement of pT153 in tau toxicity, the current project could identify novel approaches to block tau-mediated neurodegeneration in AD and related disorders.