Abstract
In Alzheimer’s disease (AD), neurofibrillary tangles (NFTs), lesions composed of hyperphosphorylated and aggregated tau, spread from the transentorhinal cortex to the hippocampal formation and neocortex. Growing evidence indicates that tau pathology propagates trans-synaptically, implying that pathological tau released by pre-synaptic neurons is taken up by post-synaptic neurons where it accumulates and aggregates. Observations such as the presence of tau in the cerebrospinal fluid (CSF) from control individuals and in the CSF of transgenic mice overexpressing human tau before the detection of neuronal death indicate that tau can be secreted by neurons. The increase of tau in the CSF in pathological conditions such as AD suggests that tau secretion is enhanced and/or other secretory pathways take place when neuronal function is compromised. In physiological conditions, extracellular tau could exert beneficial effects as observed for other cytosolic proteins also released in the extracellular space. In such a case, blocking tau secretion could have negative effects on neurons unless the mechanism of tau secretion are different in physiological and pathological conditions allowing the prevention of pathological tau secretion without affecting the secretion of physiological tau. Furthermore, distinct extracellular tau species could be secreted in physiological and pathological conditions, species having the capacity to induce tau pathology being only secreted in the latter condition. In the present review, we will focus on the mechanisms and function of tau secretion in both physiological and pathological conditions and how this information can help to elaborate an efficient therapeutic strategy to prevent tau pathology and its propagation.
Highlights
OBSERVATIONS SUPPORTING TAU SECRETION BY NEURONSAn axonal microtubule-associated protein, accumulates both intracellularly and extracellularly in Alzheimer’s disease (AD)
Reviewed by: Luc Buee, Institut National de la Santé et de la Recherche Médicale (INSERM), France Felix Hernandez, Spanish National Research Council (CSIC), Spain
Growing evidence indicates that tau pathology propagates trans-synaptically, implying that pathological tau released by pre-synaptic neurons is taken up by post-synaptic neurons where it accumulates and aggregates
Summary
An axonal microtubule-associated protein, accumulates both intracellularly and extracellularly in AD. Neuronal activity was shown to increase tau release by neurons both in vitro and in vivo (Pooler et al, 2013; Yamada et al, 2014). We reported that the induction of autophagy and/or lysosomal dysfunction increased the release of tau by primary cortical neurons (Mohamed et al, 2014). We recently reported that tau secretion induced by neuronal hyperactivity was associated with Golgi fragmentation indicating that Golgi membranes may play a role in tau secretion (Mohamed et al, 2017). Starvation, lysosomal dysfunction and hyperactivity) (Pooler et al, 2013; Mohamed et al, 2014, 2017) Both non-vesicular (free-tau) and vesicular (vesicle/exosome-tau) mechanisms were shown to contribute to tau secretion (Figure 1)
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