Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.

BACKGROUND: Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.

OBJECTIVE: This study investigated the potential therapeutic effects of the Yin Huang Ge compound on cognitive function in a mouse model of AD and evaluated its efficacy in mitigating Aβ accumulation, a key pathological feature of AD.

METHODS: APP/PS1 mice were randomly assigned to the following groups: Controls (C57BL/6 J mice) group, the Model group, YHG group, and donepezil (DNP) group. The YHG group and the DNP group were administered their respective drugs through gastric gavage, whereas the normal group and the Model group were supplied with saline. Administration sustained for a period of 30 consecutive days. We assessed mouse learning, memory, and spatial cognition using the Morris water maze, novel object recognition, Y-maze spontaneous alternation, and novel arm tests. Western blotting quantified the protein levels of β-amyloid 1-42 (Aβ1-42), insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). ELISA measured IDE and NEP enzymatic activity, while immunohistochemistry evaluated the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).

RESULTS: In contrast to the Control group, mice in the Model group exhibited significant impairments in learning, memory, and spatial cognition. The protein expression levels of Aβ1-42, MMP-2, and MMP-9 were markedly elevated (p < 0.01), whereas the expression of IDE and NEP was significantly reduced (p < 0.05, p < 0.01). ELISA analysis further revealed a substantial decrease in IDE and NEP activity (p < 0.01). A concomitant reduction in the expression of NT-3 and BDNF was also observed (p < 0.01). Compared to the Model group, mice treated with YHG or DNP exhibited significantly improved learning, memory, and spatial cognition. The protein expression of Aβ1-42, MMP-2, and MMP-9 was reduced (p < 0.05, p < 0.01), whereas the expression of IDE and NEP was elevated (p < 0.05). ELISA results confirmed the increased activity of IDE and NEP (p < 0.05). These assays also revealed a marked upregulation in the expression of NT-3 and BDNF (p < 0.01).

CONCLUSION: The YHG compound reduces cerebral Aβ deposition via a bidirectional regulatory mechanism, upregulating IDE and NEP to promote clearance while downregulating MMP-2 and MMP-9 to mitigate associated damage. It also elevates the expression of the neurotrophic factors BDNF and NT-3, which enhances endogenous neuroprotection and ameliorates core Alzheimer's disease pathology. Consequently, this treatment markedly improves cognitive function in APP/PS1 mice.