Autophagy has been reported to play a dual "double-edged sword" role in the occurrence and development of Alzheimer's disease (AD). To assess the relationship between AD and autophagy, the dynamic changes of autophagic flux in the brain of postmortem AD patients, animal models and cell models were studied. The results showed that autophagosomes (APs) accumulation and expression of lysosomal markers were decreased in the brains of AD patients. In the brain of APP/PS1 double transgenic mice, APs did not accumulate before the formation of SPs but accumulated along with the deposition of SPs, as well as the level of lysosomal markers cathepsin B and Lamp1 protein decreased significantly. In the brains of APP/PS1/LC3 triple-transgenic mice, the number of APs increased with age, but the number of ALs did not increase accordingly. The activation of autophagy is mainly due to the increase in Aβ rather than the overexpression of mutated APP gene. However, both the treatment with exogenous Aβ25-35 and the mutation of the endogenous APP gene blocked the fusion of APs with lysosomes and decreased lysosomal functioning in AD model cells, which may be the main mechanism of autophagy dysregulation in AD.

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Epidemiologic studies have demonstrated that women account for two-thirds of Alzheimer’s disease (AD) cases, for which the decline in circulating gonadal hormone is considered to be one of the major risk factors. In addition, ovarian hormone deficiency may affect β-amyloid (Aβ) deposition, which has a close relationship with autophagic flux. In this study, we investigated the impact of short-term or long-term ovarian hormone deprivation on two mouse models, the non-transgenic (wild-type) and the APP/PS1 double-transgenic AD (2×TgAD) model. Autophagy-related proteins (Beclin1, LC3, and p62) and lysosome-related proteins were detected to evaluate Aβ deposition and autophagy. Our results showed that in the group with short-term depletion of ovarian hormones by ovariectomy (ovx), Beclin1, Cathepsin B (Cath-B), and LAMP1 levels were significantly decreased, while the levels of LC3-II and p62 were increased. In the long-term group, however, there was a sharp decline in Beclin1, LC3-II, Cath-B, and LAMP1 expression but not in p62 expression which is increased. It is worthwhile to note that the occurrence of neuritic plaque-induced ovarian hormone loss increased both the Aβ level and neuritic plaque deposition in 2×TgAD mice. Therefore, autophagy may play an important role in the pathogenesis of female AD, which is also expected to help post-menopausal patients with AD.