Modeling Alzheimer's disease in mice: Gonadectomy combined with bilateral hippocampus dentate gyrus injection of Aβ oligomers.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.

New Method: This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.

Results: As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.

Comparison With Existing Methods: Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.

Conclusions: The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.

Significance Statement: In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.