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.

Icahn School of Medicine at Mount Sinai · biorxiv

Paper

Abstract

APPE693Q transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of A{beta} (NFA-A{beta}) and APP -carboxy terminal fragments. The APPE693Q mutation disrupts amyloid fibril formation, and no plaques develop in these mice. In the current study, the aging-related accumulation of NFA-A{beta} in APPE693Q mice was revealed by A11 immunohistochemistry and NFA-A{beta}-detecting cyclic D,L--peptide-FITC microscopy. The presynaptic termini of APPE693Q 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 incomplete clinical response to fibrillar A{beta} immunodepletion in human patients may be attributable to residual NFA-A{beta} that are undetectable by currently available biofluid analysis or neuroimaging of biomarkers. The depletion or neutralization of both fibrillar and NFA-A{beta} may be needed for complete elimination of A{beta} toxicity.

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Research summary

The study suggests that the accumulation of nonfibrillar Aβ aggregates contributes to synaptic dysfunction in aging, which may be a root cause of cognitive decline. This research is relevant as it explores mechanisms underlying aging-related cognitive deficits, potentially addressing fundamental aspects of age-related diseases.

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