RESUMEN
α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Ratones , Ratones Noqueados , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , alfa-Sinucleína/genética , Proteínas tau/genéticaRESUMEN
Tauopathies are a major group of neurodegenerative proteinopathies characterized by the accumulation of abnormal and hyperphosphorylated tau proteins in the brain. Tau pathology is characterized as 3R (repeat) or 4R predominant or mixed 3R and 4R type. Here we report three cases lacking mutations in the microtubule associated protein tau (MAPT) gene with unusual tau pathology. The age at onset and duration of illness, respectively, were 63 and 20 years (male), 67 and 5 years (female) and 72 and 20 years (female). The clinical presentation was compatible with a diagnosis of progressive supranuclear palsy (PSP) in two subjects and with cognitive decline in all three subjects. Common neuropathological features included neuronal loss in the hippocampus and dentate gyrus associated with spherical basophilic Pick body-like inclusions showing 4R tau immunoreactivity, which was supported by the detection of predominantly 4R tau species by Western blot examination. In addition, accumulation of tau immunoreactive argyrophilic astrocytes in the hippocampus and amygdala and oligodendroglial coiled bodies in the hippocampal white matter were observed. These morphologies appeared in combination with Alzheimer disease-related pathology and subcortical tau pathology compatible with PSP. Together with a single case report in the literature, our observations on these three cases expand the spectrum of previously described tauopathies. We suggest that this tauopathy variant with hippocampal 4R tau immunoreactive spherical inclusions might contribute to the cognitive deficits in the patients reported here. The precise definition of the clinicopathological relevance of these unusual tau pathologies merits further study.
Asunto(s)
Hipocampo/metabolismo , Hipocampo/patología , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Tauopatías/metabolismo , Tauopatías/patología , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Resultado Fatal , Femenino , Humanos , Masculino , Fenotipo , Tauopatías/diagnóstico , Tauopatías/genética , Proteínas tau/metabolismoRESUMEN
OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease. METHODS: Detailed neuropathological examination using 70µm and traditional 6µm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. RESULTS: Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. INTERPRETATION: Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.
Asunto(s)
Corteza Cerebral/patología , Sistema Límbico/patología , Enfermedad de Pick/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Benzotiazoles , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad de Pick/metabolismo , Enfermedad de Pick/fisiopatología , Coloración y Etiquetado , TiazolesRESUMEN
OBJECTIVE: To identify plasma-based biomarkers for Parkinson disease (PD) risk. METHODS: In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n = 134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging was performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. RESULTS: One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1; p = 0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards, p < 0.001, hazard ratio = 0.742). The association between plasma ApoA1 levels and age at PD onset was replicated in an independent cohort of PD patients (p < 0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p = 0.037). INTERPRETATION: Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk.