Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation DOI Open Access
Emilie L. Castranio, Merina Varghese, Elentina K. Argyrousi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

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

Language: Английский

Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation DOI Open Access
Emilie L. Castranio, Merina Varghese, Elentina K. Argyrousi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

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

Language: Английский

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