Endogenously generated Dutch‐type Aβ non‐fibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation

BACKGROUND APP E693Q (“Dutch”) transgenic mice develop aging‐related learning deficits and accumulate endogenously generated non‐fibrillar aggregates (NFAs) of amyloid beta (Aβ) and amyloid precursor protein α‐carboxy terminal fragments. NFA‐Aβ correlates with synaptic loss and memory deficits more closely than does fibrillar Aβ. METHODS We assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch Aβ in brains of APP E693Q mice. RESULTS Aging‐related accumulation of NFA‐Aβ in APP E693Q mice was revealed by A11 immunohistochemistry and cyclic D,L‐α‐peptide‐fluorescein‐5‐isothiocyanate microscopy. Presynaptic termini of APP E693Q mice developed physiological abnormalities in post‐tetanic potentiation, synaptic fatigue, synaptic vesicle replenishment, and an aging‐related reduction in mitochondrial complex I activity. Single‐cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving “protein translation” and “oxidative phosphorylation.” DISCUSSION Accumulation of NFA‐Aβ alters neuronal metabolism but does not activate inflammation. Depletion of all forms of Aβ may be required to eliminate Aβ toxicity with anti‐amyloid antibodies.