Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.

Cholinergic dysfunction and impaired synaptic plasticity are key mechanisms underlying cognitive decline in neurodegenerative conditions, including Alzheimer’s disease (AD). Schisandra chinensis pomace (SSP), a by-product of fruit processing, contains bioactive lignans and polyphenols with reported neuroprotective properties; however, its effects under cholinergic dysfunction have not been systematically investigated. In this study, the effects of SSP on scopolamine-induced cognitive impairment were evaluated using ex vivo electrophysiological and in vivo behavioral approaches. Multi-electrode array recordings demonstrated that SSP at 0.1 mg/mL significantly restored scopolamine-suppressed hippocampal long-term potentiation (LTP), whereas a higher concentration (1.0 mg/mL) did not restore hippocampal synaptic potentiation. In vivo, C57BL/6N mice received oral SSP (50 or 100 mg/kg/day) for six weeks, with scopolamine administered during the final three weeks. SSP at 50 mg/kg prevented scopolamine-induced body weight loss, attenuated hyperlocomotor activity, and significantly improved memory retention, as evidenced by enhanced performance in the passive avoidance and Morris water maze tests. Furthermore, SSP restored hippocampal brain-derived neurotrophic factor (BDNF) expression and reduced the p-JNK/JNK ratio, indicating modulation of neurotrophic and stress-responsive signaling pathways. Collectively, these findings suggest that SSP attenuates scopolamine-induced cholinergic dysfunction, accompanied by improved hippocampal synaptic plasticity and changes in BDNF and JNK signaling. These results support the potential of SSP as a neuroactive botanical resource under cholinergic challenge.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social deficits, repetitive behaviors, and heightened anxiety. Despite extensive research, effective interventions targeting core symptoms remain limited. Gami-Guibitang (GBT), a traditional herbal formula, has been clinically prescribed for anxiety-related symptoms and cognitive complaints, yet its effects on ASD-associated behavioral and molecular abnormalities have not been fully elucidated. Objective: This study aimed to evaluate the anxiolytic and neuroregulatory effects of GBT in a valproic acid (VPA)-induced ASD mouse model, focusing on behavioral outcomes and hippocampal synaptic protein expression. Methods: Pregnant C57BL/6N mice received a single intraperitoneal injection of VPA (500 mg/kg) at embryonic day 12.5. Male offspring were administered GBT (150 mg/kg, p.o.) twice daily for 4 weeks from postnatal day 21 (PND 21). These mice were behaviorally evaluated by the open-field test, elevated plus maze, marble-burying test, Y-maze, three-chamber social interaction test, and Morris water maze. Western blot analysis was conducted to examine hippocampal expression of phosphorylated and total CREB and GluR1, PI3K/Akt signaling components, as well as GABRA1 and GABRB1. Results: VPA-exposed offspring exhibited increased anxiety-like behaviors, altered repetitive behaviors, dysregulated exploratory activity, and impaired spatial learning, and reduced spontaneous alternation performance in the Y-maze. GBT reduced anxiety-like behaviors in the elevated plus maze and marble burying tests, partially improved spatial learning acquisition in the Morris water maze, and normalized excessive locomotor activity, without significantly affecting short-term working memory performance. At the molecular level, GBT significantly attenuated VPA-induced hyperphosphorylation of CREB, GluR1, PI3K, and Akt, indicating suppression of aberrant synaptic signaling rather than global enhancement. In addition, GBT increased GABRA1 expression toward control levels and enhanced GABRB1 expression beyond baseline, suggesting selective modulation of GABAergic receptor subunit composition rather than simple normalization. Conclusions: These findings provide preclinical evidence that GBT alleviates anxiety-like behavior and modulates hippocampal synaptic signaling disrupted by prenatal VPA exposure. By attenuating aberrant excitatory signaling and selectively regulating GABAergic receptor balance, GBT may represent a multi-target herbal candidate for modulating ASD-associated emotional dysregulation and domain-specific cognitive dysfunction, rather than acting as a broad cognitive enhancer.

Alzheimer’s disease (AD) is a complex pathological process that incurs significant societal costs, yet effective treatments have not yet been developed. Novel compounds targeting β-amyloid, based on the amyloid cascade hypothesis, have failed to demonstrate clinical efficacy. Among natural products with diverse mechanisms, components contained in Astragali radix have shown anti-dementia effects in various preclinical studies, including improved cognitive function, reduced β-amyloid levels, and decreased insulin resistance. This study administered a water-extracted roasted Astragali radix (RA) to 3-month-old female 5xFAD mice for 3 months, observing changes in cognitive behavior, blood glucose, and neural signaling. RA lowered glucose levels, improved working memory, fear avoidance memory, and spatial memory, and reduced anxiety behavior in 5xFAD mice. In the hippocampus, the protein expression of BDNF and p-CREB/CREB was increased, while p-JNK/JNK was decreased. The effects of RA were similar to unroasted Astragali radix in 5xFAD mice, with some components being more abundant. Therefore, RA enhances its taste and aroma, making it suitable for long-term consumption in the form of tea, which could be effective in preventing neurodegenerative diseases such as dementia.

Alzheimer's disease(AD) is a complex pathological process that incurs significant societal costs, yet effective treatments have not yet been developed. Novel compounds targeting β-amyloid, based on the amyloid cascade hypothesis, have failed to demonstrate clinical efficacy. Among natural products with diverse mechanisms, components contained in Astragali Radix (AR) have shown anti-dementia effects in various preclinical studies, including improved cognitive function, reduced β-amyloid levels, and decreased insulin resistance. This study administered a water-extracted roasted AR to 3-month-old female 5xFAD mice for 3 months, observing changes in cognitive behavior, blood glucose, and neural signaling. Roasted AR lowered glucose levels, improved working memory, fear avoidance memory, and spatial memory, and reduced anxiety behavior in 5xFAD mice. In the hippocampus, the protein expression of BDNF and p-CREB/CREB was increased, while p-JNK/JNK was decreased. The effects of roasted AR were similar to unroasted AR in 5xFAD mice, with some components being more abundant. Therefore, roasting AR enhances its taste and aroma, making it suitable for long-term consumption in the form of tea, which could be effective in preventing neurodegenerative diseases such as dementia.

Ji Hye Yoon, Seung-Yun Cha, Sungho Maeng, Yongjin Shin, Myeongae Park, and Jinkyung Kim. Journal of the Korean Society of Food Science and Nutrition 2024;53:1239-44. https://doi.org/10.3746/jkfn.2024.53.12.1239