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

Antonio Piras,Fiona Grüninger,Annica Rönnbäck,Caroline Graff,Ludovic Collin

doi:10.1186/s40478-016-0292-9

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.

Highlights

The accumulation of insoluble proteins within neurons and glia cells is a pathological hallmark of several neurodegenerative diseases
Increased levels of the lysosomal marker lysosomal-associated membrane protein 1 (LAMP1) was detected in familial AD (FAD) and corticobasal degeneration (CBD), and in addition Cathepsin D was diffusely spread in the cytoplasm in all tauopathies suggesting an impaired lysosomal integrity
Characterization of tau pathology in frontal cortex from patients diagnosed with different tauopathies Human post-mortem brain tissue from cases with earlyonset FAD, CBD, progressive supranuclear palsy (PSP) and control individuals without neurodegeneration was analysed by immunohistochemistry to determine the presence of hyperphosphorylated tau using two different phospho-tau antibodies: clone AT8 and Tau/pS422 (Additional file 1: Figure S1)

Summary

Introduction

The accumulation of insoluble proteins within neurons and glia cells is a pathological hallmark of several neurodegenerative diseases. Abnormal intracellular aggregation and accumulation of the microtubule-associated protein tau is a common feature of many neurodegenerative disorders, including Alzheimer disease (AD), frontotemporal lobar degeneration, Picks disease, argyrophilic grain disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) [3]. These neurodegenerative disorders are referred to as tauopathies. Phosphorylation of tau at serine 422 (Tau/ pS422) prevents tau cleavage by caspase-3 at aspartic acid 421 (D421), precluding tau degradation by the autophagy-lysosome system [21] Taken together these observations suggest that the autophagy-lysosome pathway plays an important role in the clearance of hyperphosphorylated tau. We showed that the autophagy-lysosomal system is impaired in patients with primary tauopathies suggesting that autophagic defects are a common feature of human tauopathies

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