TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

The role of the ATP-Binding Cassette transporter A1 in Alzheimer Disease neuropathology and brain lipoprotein metabolism

The ATP-Binding Cassette transporter A1 (ABCA1) is a ubiquitously expressed protein that mediates the efflux of cholesterol and phospholipids from the plasma membrane onto lipid poor apolipoproteins (apos), such as apoA-l and apoE. Outside the central nervous system (CNS), this process constitutes the rate-limiting step in the generation of high-density lipoproteins (HDL). Low levels of HDL and cellular lipid accumulation are the hallmarks of Tangier disease, a genetic disease caused by mutations in the ABCA1 gene. ABCA1 is also expressed in the brain, the most cholesterol rich organ in the body. However, previous to this thesis, the role of ABCA1 in brain cholesterol metabolism had been poorly explored. Furthermore, recent data indicated that disturbances in cholesterol homeostasis in the CNS may play an important pathogenic role in the development of Alzheimer Disease (AD). This, in turn, suggested that ABCA1 may also affect the progression of AD. The overall goal of this work is to gain insights into the role of ABCA1 in the development of AD neuropathology and brain lipoprotein metabolism. This thesis presents original data showing that ABCA1 deficiency results in a dramatic reduction in brain apoE levels. Because apoE has a demonstrated role in amyloid deposition, we also studied the effects of ABCA1 deficiency on amyloidogenesis in AD transgenic mice. We found that the absence of ABCA1 results in increased amyloid deposition despite low levels of apoE. The observation that ABCA1-deficiency is proamyloidogenic raised the question whether ABCA1 overexpression may reduce amyloid formation. We thus evaluated AD neuropathology in AD mice crossed to an ABCA1 bacterial artificial chromosome (BAC) transgenic mouse model. We found that although ABCA1 expression and apoE levels are elevated in the brains of ABCA1 BAC mice compared to non-transgenic controls, these effects were abolished in the presence of AD transgenes. This suggests that overexpression ofphysiologically regulated ABCA1 may be altered in brains with amyloid deposits compared to amyloid-free brains. These studies thus constitute original contributions to our understanding of the role of ABCA1 in brain lipid metabolism, and highlight the mechanisms by which ABCA1 may impact the development of AD neuropathology in vivo.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Detailed neuropathologic report of COVID-19 complicated by large intracerebral hemorrhage and periventricular lesions with macrophagic infiltrates

Infection with the SARS-CoV-2 virus affects a wide range of systems. Significant involvement of the central nervous system has been described, including ischemic and hemorrhagic strokes. Thus far, neuropathologic reports of patients who passed away from COVID-19 have generally described non-specific findings, such as variable reactive gliosis and meningeal chronic inflammatory infiltrates, as well as the consequences of the infection’s systemic complications on the brain, including ischemic infarcts and hypoxic/ischemic encephalopathy. The neuropathological changes in patients with COVID-19 and large hemorrhagic strokes have not been described in detail. We report the case of an elderly male who had a long course of COVID-19 and ultimately passed away from a large intracerebral hemorrhage. In addition to acute hemorrhage, neuropathologic examination demonstrated non-specific reactive changes and chronic periventricular lesions with macrophagic and perivascular lymphocytic infiltrates without evidence of demyelination or presence of SARS-CoV-2 by PCR test. This manuscript expands the spectrum of reported neuropathological changes in patients with COVID-19.Medicine, Faculty ofNon UBCPathology and Laboratory Medicine, Department ofReviewedFacultyResearche

Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS).

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is an uncommon cause of frontotemporal dementia characterized by fused in sarcoma-positive inclusions. It is classified as a subtype of frontotemporal lobar degeneration with FUS pathology. Cases with aFTLD-U pathology typically display an early onset of symptoms and severe psychobehavioral changes in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. This phenotype is regarded as being sufficiently unusual and consistent as to allow antemortem diagnosis with a high degree of accuracy. In this report, we describe 2 cases with aFTLD-U pathology that broaden the associated phenotype to include later age of onset, milder behavioral abnormalities and early memory and language impairment

Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS).

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is an uncommon cause of frontotemporal dementia characterized by fused in sarcoma-positive inclusions. It is classified as a subtype of frontotemporal lobar degeneration with FUS pathology. Cases with aFTLD-U pathology typically display an early onset of symptoms and severe psychobehavioral changes in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. This phenotype is regarded as being sufficiently unusual and consistent as to allow antemortem diagnosis with a high degree of accuracy. In this report, we describe 2 cases with aFTLD-U pathology that broaden the associated phenotype to include later age of onset, milder behavioral abnormalities and early memory and language impairment

Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1–/– mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe–/– mice: there was significantly less amyloid β-peptide (Aβ) deposition, a redistribution of Aβ to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S–positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD