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ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Cellular and Molecular Mechanisms of Brain-aging
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1569181
Amyloid-beta peptide toxicity in the aged brain is a one-way journey into Alzheimer's disease
Provisionally accepted
Georgia Culley
Alexandre Henriques*
Delphine HardyAlexandre Wojcinski
Adrien Chabert
Bilal El Waly
Philippe Léon Louis POINDRON
Noelle Callizot- Neuro-Sys, Gardanne, France
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Aging is the primary risk factor for Alzheimer’s disease (AD), and the aging brain shares many characteristics with the early stages of AD. This study investigates the interplay between aging and amyloid-beta (Aβ) induced pathology. We developed an AD-like in vivo model, using the stereotactic injection of Aβ1-42 oligomers into the hippocampi of aged mice. Cognitive impairments were assessed using a Ymaze. Immunohistochemical and protein analyses were conducted to evaluate neuronal survival, synaptic function and number, levels of tau hyperphosphorylation, microglial activation, autophagy, and mitochondrial function. We compared baseline aging effects in young adult (3 months) and aged (16-18 months) healthy mice. We found that aged mice displayed significant deficits in working memory, synaptic density and neurogenesis, and an increased basal inflammation. In response to acute injury to the hippocampus with Aβ oligomer injection, aged mice suffered sustained deficits, including impaired cognitive function, further reduced neurogenesis and synaptic density, increased microglial activation, astrogliosis, mitochondrial stress, and lysosomal burden. Furthermore, in the weeks following injury, the aged mice show increased amyloid accumulation, microglial activation and phosphorylated tau propagation, expanding from the injection site to adjacent hippocampal regions. In contrast, the young adult mice exhibited only acute effects without long-term progression of pathology or neurodegeneration.We conclude that the aging brain environment increases susceptibility to an acute Aβ injury, creating fertile soil for the progression of AD, whereas younger brains are able to overcome this injury. The processes of aging should be considered as an integral factor in the development of the disease. Targeting aging mechanisms may provide new strategies for AD prevention and treatment, as well as for other neurodegenerative diseases.
Keywords: Amyloid toxicity1, aging2, Alzheimer's3, Spreading4, Neurodegeneration5, Tau6, neuroinflammation7, Oligomers8
Received: 31 Jan 2025; Accepted: 07 Apr 2025.
Copyright: © 2025 Culley, Henriques, Hardy, Wojcinski, Chabert, El Waly, POINDRON and Callizot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Alexandre Henriques, Neuro-Sys, Gardanne, France
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