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Tau45-230 association with the cytoskeleton and membrane-bound organelles: Functional implications in
Sana Afreen1, D Nicole Riherd Methner1, Adriana Ferreira1
1Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abstract:
The dysregulation of posttranslational modifications of the microtubule-associated protein (MAP) tau plays a key role in Alzheimer's disease (AD) and related disorders. Thus, we have previously shown that beta amyloid (Aβ)-induced neurotoxicity was mediated, at least in part, by tau cleavage into the tau45-230 fragment. However, the mechanisms underlying the toxicity of tau45-230 remain unknown. To get insights into such mechanisms, we first determined the subcellular localization of this tau fragment in hippocampal neurons. Tau45-230 was easily detectable in cell bodies and processes extended by these neurons. In addition, cell extraction experiments performed using Triton X-100 and saponin showed that a pool of tau45-230 was associated with the cytoskeleton and the cytoskeleton plus membrane-bound organelles, respectively, in cultured hippocampal neurons. Furthermore, they suggested that these associations were independent of the presence of full-length tau. We also assessed whether this tau fragment could alter axonal transport. Our results indicated that tau45-230 significantly reduced the number of organelles transported along hippocampal axons. This altered axonal transport did not correlate with changes in the total number of organelles present in these cells or in motor protein levels. Together these results suggested that tau45-230 could exert its toxic effects by partially blocking axonal transport along microtubules thus contributing to the early pathology of AD.
Insights
The tau45-230 fragment, linked to Alzheimer's disease, disrupts axonal transport in neurons. This disruption, caused by tau cleavage, contributes to early Alzheimer's pathology.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Posttranslational modifications of microtubule-associated protein (MAP) tau are implicated in Alzheimer's disease (AD).
- Beta-amyloid (Aβ) induces neurotoxicity partly via tau cleavage into the tau45-230 fragment.
- The precise mechanisms of tau45-230 toxicity remain unclear.
Purpose of the Study:
- To investigate the subcellular localization of the tau45-230 fragment in hippocampal neurons.
- To determine the impact of tau45-230 on axonal transport.
- To elucidate the contribution of tau45-230 to early Alzheimer's disease pathology.
Main Methods:
- Subcellular localization studies using cell extraction with Triton X-100 and saponin in cultured hippocampal neurons.
- Assessment of axonal transport in hippocampal neurons treated with tau45-230.
- Analysis of organelle counts and motor protein levels.
Main Results:
- Tau45-230 was detected in the cell bodies and processes of hippocampal neurons.
- A portion of tau45-230 associated with the cytoskeleton and cytoskeleton plus membrane-bound organelles, independently of full-length tau.
- Tau45-230 significantly reduced axonal transport of organelles without altering total organelle numbers or motor protein levels.
Conclusions:
- The tau45-230 fragment localizes within hippocampal neurons and associates with cellular structures.
- Tau45-230 impairs axonal transport by partially blocking microtubule function.
- These findings suggest tau45-230 contributes to early Alzheimer's disease pathogenesis through axonal transport disruption.
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