Clearance of intracellular tau protein from neuronal cells via VAMP8-induced secretion

Abstract

In Alzheimer’s disease (AD), tau — a microtubule-associated protein — becomes hyperphosphorylated, aggregates and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid. Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether the overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using TIRF microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism (FTDP) and alpha-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and alpha-synuclein clearance to prevent their intracellular accumulation.

Immune abnormalities and differential gene expression in the hippocampus and peripheral blood of patients with Alzheimer’s disease

“…For example, Di Paolo et al (37) revealed APOB as a new link between cholesterol and AD and may underlie AD pathogenesis common to both late-onset AD and early-onset AD. VAMP8 was considered the most core gene in peripheral blood consistent with the results of a previous neuronal models study showing that VAMP8 could increase tau secretion (38). Neuroinflammation mediated by microglia and astrocytes, as well as by peripheral immune cells, has been described as an important contributor to AD (39,40).…”

Role of SNAREs in Neurodegenerative Diseases

“…Nevertheless, tau protein is also released in the extracellular space and can be found in the CSF. Secretion of tau involves transport from late endosomes to the PM and could help to prevent accumulation of the protein responsible for AD onset [ 70 ]. Vamp8 is an R-SNARE that localizes at late endosomes and that can make complexes together with syntaxin-7, vti1b and syntaxin-8 for homotypic fusion of late endosomes, with syntaxin-17 and SNAP-29 for autophagosome-lysosome fusion or with syntaxin-3 and SNAP-23 for secretion [ 45 , 77 , 78 ].…”

“…Interestingly, by overexpressing VAMP8, tau secretion was increased and the amount inside neuroblastoma cells was reduced [ 70 ]. In fact, VAMP8-, Rab7- and Rab9-positive vesicles containing tau were directed to the PM where tau was released.…”

“…Interestingly, a decreased phosphorylation level of tau was detected. Furthermore, overexpression of VAMP8 determined a reduction of the intracellular amount of mutated forms of tau associated with frontotemporal dementia with parkinsonism (FTDP) and alpha-synuclein [ 70 ]. It has also been proven that VAMP8 is involved in autophagosome-lysosome fusion [ 45 ].…”

Smuggle tau through a secret(ory) pathway

“…A related question is: What is unique about the TM domains of STX6 and STX8? The recent finding that overexpression of VAMP8a v-SNARE on late endosomescould also lead to tau secretion from neuronal cells [26] seems to imply that TM domain-mediated tau release might not be limited to syntaxins.…”