Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Area of Science:

• Neuroscience
• Alzheimer's Disease Research
• Synaptic Plasticity

Background:

• Synaptic dysfunction is a key feature of Alzheimer's disease (AD).
• Synapses possess plasticity, potentially enabling adaptation to early AD pathology.
• Cholinergic system integrity is crucial for cognitive function and is affected in AD.

Purpose of the Study:

• To investigate the presynaptic response of cholinergic neurons to tau pathology in the living human brain.
• To determine if cholinergic synaptic adaptation is associated with cognitive resilience in individuals at risk for AD.
• To explore the genetic underpinnings of cholinergic neuronal plasticity in relation to tau pathology.

Main Methods:

• Multi-tracer positron emission tomography (PET) in cognitively normal adults at risk for AD.
• Whole-brain single-nucleus RNA sequencing in human and mouse brain tissue.
• Forebrain-specific deletion of vesicular acetylcholine transporter (VAChT) in a mouse model.

Main Results:

• Cholinergic neurons increased vesicular acetylcholine transporter (VAChT) protein levels when colocalized with tau, but not amyloid.
• Higher VAChT levels in cholinergic neurons predicted preserved cognitive function over ten years.
• Cholinergic neurons exhibit a plasticity gene network linked to the MAPT gene; VAChT deletion in mice impaired plasticity and hippocampal integrity.

Conclusions:

• Cholinergic synaptic plasticity is a critical mechanism of resilience against tau pathology in presymptomatic AD.
• Failure of this adaptive plasticity contributes to vulnerability in the progression of AD.
• Targeting cholinergic synaptic mechanisms may offer therapeutic avenues for preserving cognition in early AD.