Biology subjects

Lee, V. M. Y.

Publications and source records attributed to Lee, V. M. Y..

7 recordsLinked to original sources

bioRxiv2024

Hyperactive neuronal networks facilitate tau spread in an Alzheimer's disease mouse model

Pathological tau spreads via neuronal connections in Alzheimers disease (AD). Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized that neuronal hyperactivity and seizures exacerbate tau spread. To examine the impacts of brain-wide network and population hyperactivity on tau spread, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) and the 5 times familial AD mice (5X-TRAP) that allows for the permanent labelling of seizure-activated neurons. To explore the effects of seizures on tau spread, we injected these mice with human AD brain-derived tau to induce pathological tau spread, and induced seizures with pentylenetetrazol (PTZ) kindling. Brain mapping revealed that seizures increased tau spread in 5X-TRAP mice, which correlated extensively with memory deficits in PTZ kindled 5X-TRAP mice. Using computational models, we found data supportive of increased anterograde tau spread in 5X-TRAP mice and that regional neuronal activity levels were predictive of tau pathology. On a cellular level, we found that hyperactive neurons drive elevated tau propagation in 5X-TRAP mice. We also found corroborating evidence of increased tau spread in AD patients with a seizure history compared to those without. Our study identifies neuronal hyperactivity and seizures as key, targetable factors underlying AD progression.

neuroscience↗

bioRxiv2023

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinsons disease (PD). These mutations elevate LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic target. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of LRRK2 inhibitors efficacy against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of -synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wildtype or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3 to 6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 665 brain regions and subsequent linear diffusion modeling of progression. Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice that were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wildtype mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers, but additional work may be necessary to determine the potential effect in non-carriers. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

neuroscience↗

bioRxiv2023

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.

neuroscience↗

bioRxiv2022

Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson's disease

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded -synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and disease severity. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with -synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to disease severity.

neuroscience↗

bioRxiv2022

Evaluation of Blood-Based Exosomes as Biomarkers for Aging-Related TDP-43 pathology

INTRODUCTIONLimbic predominant age related TDP-43 encephalopathy (LATE) is a recently characterized brain disease that mimics Alzheimers disease (AD) clinically. To date, LATE is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of exosomal protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. METHODSTDP-43 was evaluated in neuronal (NDE), astrocyte (ADE), and microglial derived exosomes (MDE). Exosome preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE. Quantified TDP-43 concentrations were compared to cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE. RESULTSTDP-43 was significantly elevated in plasma ADEs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in exosome depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between exosomal TDP-43 levels with cognition-based variables, sex, and APOE carrier status. DISCUSSIONBlood-based exosomes, specifically measuring TDP-43 accumulation in ADEs, may serve as a powerful diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.

neuroscience↗

bioRxiv2020

Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

Tau pathology is a diagnostic feature of Alzheimers disease (AD) but is also a prominent feature of Parkinsons disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathologys initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

neuroscience↗

bioRxiv2019

Defining and predicting transdiagnostic categories of neurodegenerative disease

In current models of neurodegeneration, individual diseases are defined by the presence of one or two pathogenic protein species. Yet, it is the rule rather than the exception that a patient meets criteria for more than one disease. This fact often remains hidden until autopsy, when neuropathological evaluation can assign disease labels based on gold-standard criteria. Ultimately, the prevalence of concomitant diagnoses and the inability to infer an underlying neuropathological syndrome from clinical variables hinders the identification of patients who might be good candidates for a particular intervention. Here, by applying graph-based clustering to post-mortem histopathological data from 1389 patients with degeneration in the central nervous system, we generate 4 non-overlapping, data-driven disease categories that simultaneously account for amyloid-{beta} plaques, tau neurofibrillary tangles, -synuclein inclusions, neuritic plaques, TDP-43 inclusions, angiopathy, neuron loss, and gliosis. The resulting disease clusters are transdiagnostic in the sense that each cluster contains patients belonging to multiple different existing disease diagnoses, who colocalize in clusters according to the pathogenic protein aggregates known to drive each disease. We show that our disease clusters, defined solely by histopathology, separate patients in terms of cognitive phenotypes, cerebrospinal fluid (CSF) protein levels, and genotype in a manner that is not trivially explained by the representation of individual diseases within each cluster. Finally, we use cross-validated multiple logistic regression to generate high accuracy predictions (AUC > 0.9) of membership to both existing disease categories and transdiagnostic clusters based on CSF protein levels and genotype, both accessible in vivo. Broadly, our approach parses phenotypic and genotypic heterogeneity in neurodegenerative disease, and represents a general framework for identifying otherwise-fuzzy disease subtypes in other areas of medicine, such as epilepsy, vascular disease, and cancer. In clinical neurology, the statistical models we generate may be useful for repurposing drugs by comparing efficacy to probabilistic estimates of disease cluster membership, as well as for future trials that could be targeted towards an algorithmically defined family of diseases.

neuroscience↗