Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Area of Science:

• Neuroscience
• Cellular Biology
• Alzheimer's Disease Pathogenesis

Background:

• Alzheimer's Disease (AD) pathogenesis involves early regional vulnerability and hyperexcitability, particularly in the entorhinal cortex, preceding cognitive decline.
• The cellular origins and regional specificity of this early hyperexcitability remain poorly understood.
• Current understanding focuses on excitatory neurons, but the precise mechanisms driving early AD pathology are unclear.

Purpose of the Study:

• To investigate the cellular mechanisms underlying early regional vulnerability and hyperexcitability in Alzheimer's Disease.
• To determine the cell type and region specificity of human amyloid precursor protein (hAPP) effects in a mouse model.
• To explore potential therapeutic targets for early-stage Alzheimer's Disease.

Main Methods:

• Utilized cell-type-specific proteomics and electrophysiology (ex vivo and in vivo) in a mouse model expressing human-specific amyloid precursor protein (hAPP).
• Compared hAPP effects in the entorhinal cortex and Somatosensory Cortex.
• Investigated the impact of modulating parvalbumin (PV) interneuron excitability and co-expression of human Tau with hAPP.

Main Results:

• Early hyperexcitability in the entorhinal cortex was linked to intrinsic vulnerability of parvalbumin (PV) interneurons, specifically in response to hAPP, not murine APP.
• Neurons in the Somatosensory Cortex did not exhibit similar vulnerability to adult-onset hAPP.
• Enhancing PV interneuron excitability ameliorated hAPP-induced hyperexcitability; co-expressing Tau with hAPP reduced hyperexcitability but increased pathological tau.

Conclusions:

• Early Alzheimer's hyperexcitability in vulnerable regions like the entorhinal cortex may originate from intrinsic deficits in PV interneurons.
• Interventions targeting PV interneurons represent a potential strategy for early Alzheimer's Disease prevention.
• Understanding cell-type-specific vulnerabilities is crucial for developing effective Alzheimer's Disease therapies.