Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation.

Abstract

APP ^E693Q transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of Aβ (NFA-Aβ) and APP α-carboxy terminal fragments. The APP ^E693Q mutation disrupts amyloid fibril formation, and no plaques develop in these mice. In the current study, the aging-related accumulation of NFA-Aβ in APP ^E693Q mice was revealed by A11 immunohistochemistry and NFA-Aβ-detecting cyclic D,L-α-peptide-FITC microscopy. The presynaptic termini of APP ^E693Q mice developed aging-related physiological abnormalities in post-tetanic potentiation, synaptic fatigue, and synaptic vesicle replenishment. Single-cell RNA sequencing showed that excitatory neurons exhibited the most altered transcriptomic profile, especially involving "protein translation" and "oxidative phosphorylation". Direct measurements of electron transport chain catalysis revealed reduction in mitochondrial complex I activity in Dutch mice. Microglial transcript analysis revealed no evidence of inflammation. The depletion or neutralization of both fibrillar and NFA-Aβ may be needed for complete elimination of Aβ toxicity.

Teaser: APP ^E693Q "NFA-Aβ only" mice reveal clinically relevant mechanisms despite the absence of detectable inflammation.