Abstract
SummaryIn Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.
Highlights
The microtubule-associated protein tau (MAPT) is involved in the pathogenesis of several forms of dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD)
Mice transgenic for human tau have 10-fold higher concentrations of tau in brain interstitial fluid than in cerebrospinal fluid (CSF), which would suggest that the extracellular concentrations of tau in the human brain are in the high picomolar-low nanomolar range (Yamada et al, 2011)
Focusing on P301S tau enabled us to study the transmission of a diseaserelevant, aggregation-prone variant that differs from normal tau by a single amino acid, comparing monomeric and aggregated forms directly
Summary
The microtubule-associated protein tau (MAPT) is involved in the pathogenesis of several forms of dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Clinical severity of symptoms, is associated with a predictable spatial and temporal order of appearance of NFTs in different forebrain regions (Braak and Braak, 1991). This has led to the proposal that these diseases actively spread from diseased to healthy neurons in a spatial and temporal progression, mediated by extracellular, abnormal, disease-associated forms of tau (Iba et al, 2013; Liu et al, 2012). There have been conflicting reports about the ability of extracellular monomeric tau to enter cells, whereas aggregated or fibrillar tau has been clearly shown to efficiently enter neurons and other cell types (Frost et al, 2009; Kfoury et al, 2012; Wu et al, 2013)
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