Selective weakening of population-coupled synaptic activity in vivo in a mouse model of amyloid-beta pathology

Nat Commun. 2026 Mar 7. doi: 10.1038/s41467-026-69866-3. Online ahead of print.

ABSTRACT

Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in App^NL-G-F mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic structure/function imaging finds reduced density and calcium-mediated activity of GABAergic axonal boutons. Rather than occurring globally, reduced synaptic activity is focused at GABAergic boutons strongly coupled to population activity in the amyloid microenvironment. The selective weakening of population-coupled synaptic activity also occurs in excitatory dendritic spines. Spatial transcriptomics finds parvalbumin-positive inhibitory neurons show differential gene expression associated with downregulated GABAergic synaptic transmission at early stages. We propose that early-stage AD-related synaptic pathophysiology is focused at population-coupled synapses, with molecular measures implicating abnormal synaptic processing as an early-stage feature in parvalbumin-positive interneurons.

PMID:41794826 | DOI:10.1038/s41467-026-69866-3