Abstract
Filamentous tau inclusions are hallmarks of Alzheimer's disease and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau-mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentration recombinant human tau (h-tau42) becomes phosphorylated, produces a rapid synaptic transmission block, and induces the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau42 does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following presynaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and identify a potential therapeutic agent to treat tau-related neurotoxicity.
Highlights
Classical neuropathological studies characterized the intracellular accumulation and aggregation of abnormal filaments composed primarily of the microtubule associated protein tau as a hallmark for a variety of neurodegenerative disorders known as tauopathies, as exemplified by progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP17; Lee et al, 2001)
The results showed that heavy exogenous h-tau42 accumulation induces a rapid and short-lasting increase in spontaneous transmitter release followed by a drastic decrease and failure of synaptic transmission
Intra-axonal h-tau42 acutely blocks synaptic transmission Following presynaptic and post-synaptic axon impalements and the determination of normal synaptic transmission (Llinas et al, 1985, 1994; Lin et al, 1990), the effect of human tau on synaptic release was evaluated by presynaptic microinjections administered under direct visualization using a fluorescent dye/ protein mix, reaching a final concentration after diffusion of approximately 80 nM
Summary
Classical neuropathological studies characterized the intracellular accumulation and aggregation of abnormal filaments composed primarily of the microtubule associated protein tau as a hallmark for a variety of neurodegenerative disorders known as tauopathies, as exemplified by progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP17; Lee et al, 2001). The most common tauopathy, Alzheimer’s disease (AD), is characterized by additional filamentous structures paired helical filaments (PHFs) and straight filaments (SFs). These filaments eventually form large aggregations, known as neurofibrillary tangles (NFTs). Mouse tauopathy studies indicate that severe abnormalities in synaptic function can precede neuronal loss and even NFTs formation (LaFerla et al, 2007; Yoshiyama et al, 2007). Neurofibrillary degeneration is accompanied by lysosomal hypertrophy (Nixon et al, 1992), beading and degeneration of distal dendrites (Braak et al, 1994; Marx, 2007) and axonal damage (Kowall and Kosik, 1987)
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