Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

TLDR

Alzheimer’s disease is a progressive neurodegenerative disorder in which neuronal dysfunction precedes amyloid‑β plaque accumulation, and understanding the timing and nature of this pre‑plaque dysfunction is essential for identifying therapeutic targets. The study aimed to examine the progression of morphological, functional, and behavioral dysfunction in the Tg2576 mouse model of AD. Researchers assessed dendritic spine density, long‑term potentiation, and contextual fear conditioning across ages in Tg2576 mice to track changes before plaque deposition. They found that dendritic spine loss, impaired LTP, and memory deficits began as early as 4–5 months, long before plaques appeared at 18 months, with an early rise in the Aβ42/Aβ40 ratio and later increases in amyloid and glial activation.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Aβ42/Aβ40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until ≈18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.