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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer's Disease (AD) presents a critical need for preventative treatments.
• Early cognitive decline in AD correlates with neuronal hyperexcitability, particularly in the entorhinal cortex (EC).
• The reasons for regional susceptibility to AD pathology remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms underlying the entorhinal cortex's early vulnerability in Alzheimer's Disease.
• To identify specific cell types and molecular factors contributing to regional hyperexcitability.

Main Methods:

• Regional, cell-type-specific proteomics in wild-type mice.
• Electrophysiological recordings to assess neuronal activity.
• Utilized human amyloid precursor protein (hAPP) and APP chimeras in mouse models.

Main Results:

• The entorhinal cortex exhibits unique susceptibility to human amyloid precursor protein (hAPP).
• Entorhinal hyperexcitability stems from selective vulnerability of parvalbumin (PV) interneurons.
• Enhancing PV interneuron excitability or co-expressing Tau with hAPP ameliorated hyperexcitability.

Conclusions:

• Early interventions targeting inhibitory neurons, like PV interneurons, may offer a protective strategy against AD pathology.
• Understanding regional vulnerability is key to developing effective preventative treatments for Alzheimer's Disease.
• APP and Tau pathology interact to influence neuronal excitability in vulnerable brain regions.