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Author Spotlight: Understanding the Impact of Pathological Proteins on Axonal Transport in Neurodegenerative Diseases
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APPsα Rescues Tau-Induced Synaptic Pathology.

Charlotte S Bold1, Danny Baltissen1, Susann Ludewig2,3

  • 1Institute of Pharmacy and Molecular Biotechnology, Ruprecht Karls Universität Heidelberg, Heidelberg, 69120, Germany.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|June 6, 2022
PubMed
Summary

Amyloid precursor protein alpha (APPsα) shows therapeutic potential for tauopathies by restoring synaptic plasticity and neuron density. This study also identified early interneuron loss as a key factor in tau-related synaptic dysfunction.

Keywords:
APPsαAlzheimer's diseaseTauhippocampusinterneuronssynaptic plasticity

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Neurodegenerative Diseases

Background:

  • Alzheimer's disease (AD) and primary tauopathies are characterized by amyloid-beta (Aβ) plaques and hyperphosphorylated Tau species.
  • Non-amyloidogenic processing of amyloid precursor protein (APP) yields APPsα, which has neurotrophic and synaptotrophic effects.
  • Previous research demonstrated APPsα's therapeutic effects in rescuing Aβ-dependent impairments in AD models.

Purpose of the Study:

  • To investigate the potential of APPsα in mitigating Tau-induced synaptic deficits in a tauopathy mouse model (P301S mice).
  • To explore the underlying mechanisms of Tau-mediated synaptic dysfunction, including changes in neuronal circuits and plasticity.
  • To assess APPsα's efficacy in restoring synaptic integrity and neuronal function in advanced stages of Tau pathology.

Main Methods:

  • Analysis of synaptic plasticity, specifically long-term potentiation (LTP), in hippocampal slices from P301S mice.
  • Acute application of APPsα to hippocampal slices to assess its rapid effects on LTP.
  • Adeno-associated virus (AAV)-mediated in vivo expression of APPsα in P301S and THY-Tau22 mice to evaluate its long-term effects on neuronal spine density.
  • Histological examination to identify changes in GABAergic interneuron subtypes in the hippocampus.
  • Behavioral tests, including nest building, to assess hippocampal function.

Main Results:

  • APPsα normalized aberrantly increased LTP in P301S mice, demonstrating a rapid homeostatic effect on synaptic plasticity.
  • In vivo APPsα expression restored normal CA1 neuron spine density in both P301S and THY-Tau22 mice, even with advanced Tau pathology.
  • A progressive loss of major GABAergic interneuron subtypes was identified in the hippocampus of P301S mice, preceding Tau accumulation.
  • This interneuron loss correlated with deficits in nest building behavior, indicating impaired hippocampal function.
  • The loss of interneurons likely disrupts neuronal circuits, compromising synaptic plasticity and behavior.

Conclusions:

  • APPsα demonstrates significant therapeutic potential for Tau-mediated synaptic dysfunction by rescuing spine loss and normalizing aberrant synaptic plasticity.
  • APPsα's therapeutic effects extend beyond synaptotrophic functions to include homeostatic regulation of neuronal network activity.
  • The study identifies the early loss of inhibitory interneurons as a critical pathological event in tauopathy, disrupting neural circuits and leading to synaptic and behavioral deficits.