Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Endogenously generated Dutch-type Aβ non-fibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation.
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Castranio Emilie L, Varghese Merina, Argyrousi Elentina K, Tripathi Kuldeep, Huang Yong, Asada Akiko, Söderberg Linda, Bresnahan Erin, Lerner David, Garretti Francesca, Zhang Hong, van de Loo Jonathan, Stimpson Cheryl D, Talty Ronan, Glabe Charles, Levy Efrat, Wang Minghui, Ilkov Marjan, Suzuki Toshiharu, Ando Kanae, Zhang Bin, Lannfelt Lars, Guérin Brigitte, Lubell William D, Rahimipour Shai, Dickstein Dara L, Gandy Sam, Arancio Ottavio, Ehrlich Michelle E
Аннотация
BACKGROUND: APPE693Q ("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 APPE693Q mice.
RESULTS: Aging-related accumulation of NFA-Aβ in APPE693Q mice was revealed by A11 immunohistochemistry and cyclic D,L-α-peptide-fluorescein-5-isothiocyanate microscopy. Presynaptic termini of APPE693Q 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.
METHODS: We assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch Aβ in brains of APPE693Q mice.
RESULTS: Aging-related accumulation of NFA-Aβ in APPE693Q mice was revealed by A11 immunohistochemistry and cyclic D,L-α-peptide-fluorescein-5-isothiocyanate microscopy. Presynaptic termini of APPE693Q 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.