APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Alzheimer's Disease Pathogenesis

Background:

• Alzheimer's disease (AD) and mild cognitive impairment (MCI) involve entorhinal cortex (EC) neuronal loss, leading to hippocampal disconnection and cognitive deficits.
• Cholinergic sprouting in the hippocampus is hypothesized to compensate for reduced EC glutamatergic input, but direct evidence is lacking.
• The APOE4 allele, a major risk factor for AD, impairs cholinergic sprouting in transgenic mouse models.

Purpose of the Study:

• To investigate the compensatory role of cholinergic sprouting in response to EC lesions.
• To explore the mechanisms underlying EC lesion-induced spatial memory deficits and network hyperactivity.
• To determine the impact of the APOE4 allele on cholinergic sprouting and functional compensation.

Main Methods:

• Utilized transgenic mice expressing the human APOE4 allele to model impaired cholinergic sprouting.
• Induced partial EC lesions and assessed spatial memory deficits and hippocampal-entorhinal network activity.
• Employed optogenetics to stimulate cholinergic fibers and modulate dentate network hyperactivity.

Main Results:

• Cholinergic sprouting was found to be necessary and sufficient for acute compensation of EC lesion-induced spatial memory deficits.
• Partial EC lesions induced abnormal hyperactivity in EC/dentate networks, which was ameliorated by cholinergic stimulation.
• APOE4 expression impaired cholinergic sprouting, correlating with deficits in compensatory mechanisms.

Conclusions:

• Cholinergic sprouting plays a critical role in the acute functional compensation of EC lesions, potentially by controlling dentate hyperactivity.
• Impaired cholinergic sprouting in APOE4 carriers may contribute to accelerated cognitive decline in MCI and AD.
• Targeting cholinergic pathways and addressing dentate hyperactivity represent potential therapeutic strategies for AD.