APPsα Rescues Tau-Induced Synaptic Pathology.

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.