Dynamic changes of hippocampal dendritic spines in Alzheimer's disease mice among the different stages

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides and a progressive decline in cognitive function. Hippocampus as a crucial brain area for learning and memory, is also adversely affected by AD's pathology. The accumulation of Aβ is often associated with the loss of dendritic spines of the hippocampus. However, the dynamic alterations in dendritic spines throughout AD progression are not fully understood. To investigate it, we conducted in-vivo imaging in two mouse models representing the early and late stages of AD pathology: young mice injected with Aβ_1–42 oligomers and APP/PS1 transgenic mice. In the early-stage AD model, imaging was conducted at third- and fifth- weeks post-injection. In the late-stage AD model, a four-month imaging began at 14 months old. The imaging results showed spine elimination in both models. Notably, acute Aβ exposure was linked to heightened spine loss on secondary dendrites, while in the late stage the primary effect was on tertiary dendrites. Concurrently, with the metabolism of Aβ, cognition recovered to some extent by five weeks post Aβ_1–42 exposure. These findings suggested that dendritic spine plasticity was impaired during the development of AD, as evidenced by increasing spine loss at different levels. However, the cognitive recovery observed in early-stage AD model mice may indicate a compensatory structural reorganization, highlighting the potential of early intervention to mitigate disease progression. Our results provide novel insights into the neurotoxic effects of Aβ_1–42 and may contribute to the development of therapeutic strategies for AD.