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

Castranio, E. L.; Varghese, M.; Argyrousi, E. K.; Tripathi, K.; Soderbergh, L.; Bresnahan, E.; Lerner, D.; Garretti, F.; Zhang, H.; van de Loo, J.; Stimpson, C.; Talty, R.; Glabe, C.; Levy, E.; Wang, M.; Ivkov, M.; Zhang, B.; Lannfelt, L.; Guerin, B.; Lubell, W.; Rahimipour, S.; Dickstein, D. L.; Gandy, S. E.; Arancio, O.; Ehrlich, M. E.

doi:10.1101/2025.02.25.639746

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bioRxiv · 10.1101/2025.02.25.639746

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

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Abstract

Structured AbstractO_ST_ABSBackgroundC_ST_ABSAPPE693Q ("Dutch") transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of A{beta} (NFA-A{beta}) and APP -carboxy terminal fragments. NFA-A{beta} correlates with synaptic loss and memory deficits more closely than does fibrillar A{beta}. MethodsWe assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch A{beta} in brains of APPE693Q mice. ResultsAging-related accumulation of NFA-A{beta} in APPE693Q mice was revealed by A11 immunohistochemistry and cyclic D,L--peptide-FITC 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". DiscussionAccumulation of NFA-A{beta} alters neuronal metabolism but does not activate inflammation. Depletion of all forms of A{beta} may be required to eliminate A{beta} toxicity with anti-amyloid antibodies.

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Castranio, E. L., Varghese, M., Argyrousi, E. K., Tripathi, K., Soderbergh, L., Bresnahan, E., Lerner, D., Garretti, F., Zhang, H., van de Loo, J., Stimpson, C., Talty, R., Glabe, C., Levy, E., Wang, M., Ivkov, M., Zhang, B., Lannfelt, L., Guerin, B., Lubell, W., Rahimipour, S., Dickstein, D. L., Gandy, S. E., Arancio, O., Ehrlich, M. E.. 2025-02-26. Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation. https://doi.org/10.1101/2025.02.25.639746

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