Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy

Abstract

IntroductionThe accumulation of insoluble proteins within neurons and glia cells is a pathological hallmark of several neurodegenerative diseases. Abnormal aggregation of the microtubule-associated protein tau characterizes the neuropathology of tauopathies, such as Alzheimer disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). An impairment of the lysosomal degradation pathway called macroautophagy, hereafter referred to as autophagy, could contribute to the accumulation of aggregated proteins. The role of autophagy in neurodegeneration has been intensively studied in the context of AD but there are few studies in other tauopathies and it is not known if defects in autophagy is a general feature of tauopathies. In the present study, we analysed autophagic and lysosomal markers in human post-mortem brain samples from patients with early-onset familial AD (FAD) with the APP Swedish mutation (APPswe), CBD and PSP and control individuals.ResultsFAD, CBD and PSP patients displayed an increase in LC3-positive vesicles in frontal cortex, indicating an accumulation of autophagic vesicles. Moreover, using double-immunohistochemistry and in situ proximity ligation assay, we observed colocalization of hyperphosphorylated tau with the autophagy marker LC3 in FAD, CBD and PSP patients but not in control individuals. Increased levels of the lysosomal marker LAMP1 was detected in FAD and CBD, and in addition Cathepsin D was diffusely spread in the cytoplasm in all tauopathies suggesting an impaired lysosomal integrity.ConclusionTaken together, our results indicate an accumulation of autophagic and lysosomal markers in human brain tissue from patients with primary tauopathies (CBD and PSP) as well as FAD, suggesting a defect of the autophagosome-lysosome pathway that may contribute to the development of tau pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0292-9) contains supplementary material, which is available to authorized users.

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Thus, these protein homeostasis mechanisms may function differently to affect diverse pathological symptoms in familial vs. sporadic AD. In support of this notion, recent studies have demonstrated that familial AD bearing more mitochondrial unfolded protein response (mtUPR) gene activation (around 70%–90%) compared to sporadic AD (around 40%–60%), indicating that at least mtUPR is more relevant in pathogenesis of familial AD (Piras, Collin, Grüninger, Graff, & Rönnbäck, 2016). …”

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

“…Similarly, in a drosophila model of tauopathy, neurodegeneration can still be seen in the absence of neurofibrillary tangle formation (Wittmann et al , 2001). Interestingly, It has been hypothesized that one reason oligomeric tau is able to accumulate in tauopathies is due to the fact that both oligomeric tau and cleaved forms of tau, which have an increased propensity for aggregation compared to full-length tau, are preferentially degraded via autophagy (Chesser et al , 2013), a pathway reported to be defective in tauopathies (Piras et al , 2016) and TBI (Sarkar et al , 2014). Although proteasome dysfunction, the mechanism which preferentially degrades monomeric tau, has also been reported to occur following TBI due to mechanisms such as oxidative stress (Bader and Grune, 2006; Weih et al , 2001; Yao et al , 2008), monomeric full-length tau has a decreased propensity to aggregate compared to cleaved tau (Chesser et al , 2013) and is less toxic than oligomeric tau (Spires-Jones et al , 2011).…”

Síndrome da Paralisia Supranuclear Progressiva: As dificuldades de diagnóstico e a atuação da Equipe multidisciplinar quanto aos cuidados à pessoa afetada por esta doença

“…Em condições normais, a tau é predominantemente expressa em axônios neuronais, cuja função principal é promover a montagem de microtúbulos e estabilização, o que é importante para a manutenção do transporte axonal e integridade neuronal Caracteriza-se por distúrbios neurodegenerativos em que a tau é depositada no cérebro. Há diferentes morfologias de agregados de tau observadas, incluindo emaranhados neurofibrilares, astrocitos tufados (TAs), corpos enrolados e linhagens patológicas (Ishiki, et al, 2017;Piras, Collin, Grüninger, Graff, & Rönnbäck, 2016).…”

“…Outro processo referido na literatura trata-se da agregação intracelular anormal e a acumulação da proteína tau associada aos microtúbulos que envolve o conjunto de doenças degenerativas coletivas de desordens neurodegenerativas, dentre elas, a PSP, mas que ainda não são compreendidas, mas se sugere que há modificações pós-translacionais anormais, tais como hiperfosforilação e acetilação, e degradação prejudicial de tau por meio dos sistemas ubiquitina-proteassoma (UPS) e autofagia-lisossoma (Piras, Collin, Grüninger, Graff, & Rönnbäck, 2016).…”

“…A autofagia é um processo altamente regulado que envolve o sequestro de carga citoplasmática, como proteínas agregadas e organelas danificadas, dentro de vesículas de membrana dupla chamadas autofagosomas, que são rotuladas tipicamente pela proteína associada a microtúbulos. A autofagia funcional é crucial para a fisiologia neuronal e a perda desta no sistema nervoso central conduz à neurodegeneração (Piras, Collin, Grüninger, Graff, & Rönnbäck, 2016 Para determinar o diagnóstico referente à PK, devem existir ao menos dois traços, dentre eles, identificáveis como sinais clínicos de rigidez, bradicinesia, tremor, e instabilidade postural, mas a presença de dois deles é necessária para defini-lo, e um desses dois sinais, como dito antes, deve ser tremor ou rigidez (Vasconcellos, 2009). …”