Alzheimer’s — can plants offer hope for better memory?

Aim of the study: Salvia officinalis L. and Salvia lavandulaefolia L.

Results: S. officinalis and S. lavandulaefolia have beneficial effects, improving cognitive performance in both healthy people and patients with dementia or cognitive impairment, and are safe for this use. Unfortunately, these promising benefits are undermined by methodological issues, the use of different herbal preparations (extracts, essential oil, or raw material), and a lack of details about the herbal products used. We believe that the promising effects of sage need to be examined in further clinical trials with higher methodological standards.

Aim of the study: Background: The prevalence of mild cognitive impairment (MCI) is estimated at 6%–12% of the population. Early treatment at the MCI stage may reduce progression to more severe cognitive impairment.

Results: Two studies that tested the same Chinese herbal medicine (CHM) formula, Bu Yang Huan Wu Tang, in combination with donepezil, reported improvement in the groups receiving the combined treatment. However, the studies were not blinded and lasted only 8–12 weeks. Overall, methodological weaknesses limited the strength of the evidence. The herbal formulas included ingredients that have received considerable research attention for their effects on memory and cognition. PROSPERO international prospective register of systematic reviews protocol registration number: CRD42018099650.

Aim of the study: Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin.

Results: Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research. Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2021137.

Aim of the study: The safety and therapeutic effects of Gingko biloba extract EGb 761® to treat cognitive decline have been demonstrated in numerous clinical trials. However, trials in Indian populations have been lacking.

Results: After 18 weeks, significant improvements compared with baseline were found in constructional praxis (CERAD CP, p < 0.0001), memory (CERAD recall of CP, p < 0.0001), speed and executive functioning (TMT A, p < 0.0001; TMT B, p < 0.0001), and behavioral symptoms (BEHAVE-AD, p < 0.0001). A total of 45 adverse events were reported in 33 (22.0%) patients, including ten suspected adverse drug reactions in 9 (6.0%) patients. Mild-to-moderate headache and diarrhea were the most frequent events. Two serious adverse events, both considered unrelated to the study drug, occurred in 2 (1.3%) patients. This study confirmed the favorable safety profile and suggested therapeutic benefits of EGb 761® in Indian patients with major neurocognitive disorder.

Aim of the study: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, the formation of amyloid-β plaques and neurofibrillary tangles, and synaptic dysfunction. Puerarin (PUE), an isoflavone C-glycoside extracted from Pueraria lobata, has demonstrated potential in attenuating AD-related cognitive decline; however, the mechanisms governing the effects of PUE remain incompletely understood.

Results: PUE administration reversed memory impairment and enhanced both hippocampal long-term potentiation and synaptic transmission by increasing the open probability of N-methyl-D-aspartate receptor (NMDAR) channels. Furthermore, PUE elevated D-serine levels and upregulated the expression of SR. Notably, these therapeutic effects were replicated by exogenous D-serine and abolished by treatment with an SR inhibitor. These findings indicate that PUE alleviates cognitive deficits by promoting SR-mediated D-serine biosynthesis and subsequently restoring NMDAR activity. Accordingly, PUE represents a viable therapeutic candidate for the prevention and management of AD.

Aim of the study: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological accumulation of amyloid-β (Aβ). Hippocampal aromatase (AROM), a key enzyme for local estrogen biosynthesis, has emerged as an important regulator of Aβ metabolism.

Results: HLJD significantly improved learning and memory deficits and reduced hippocampal Aβ accumulation in APP/PS1 mice without altering APP expression. In both in vivo and in vitro models, HLJD significantly upregulated AROM expression. HLJD suppressed Aβ production by downregulating BACE1 while enhancing Aβ degradation through upregulation of IDE and NEP. Importantly, AROM knockdown largely abolished the regulatory effects of HLJD on Aβ metabolism, whereas AROM overexpression reproduced its protective actions. These findings demonstrate that HLJD alleviates cognitive impairment in AD models by activating hippocampal aromatase and restoring Aβ homeostasis through coordinated regulation of Aβ production and degradation. This study identifies AROM as a critical mediator of HLJD's neuroprotective effects and highlights AROM-dependent modulation of local estrogen synthesis as a promising therapeutic strategy for Alzheimer's disease.

Aim of the study: Ziziphora clinopodioides Lam. (Z. clinopodioides), a distinctive medicinal plant endemic to Xinjiang, is predominantly centers on cardiovascular diseases. However, its possible therapeutic value in neurologic conditions have not been thoroughly examined, especially in Alzheimer's disease (AD). This study elucidates the intervention effect and mechanism of Z. clinopodioides on cognitive dysfunction in vivo and in vitro.

Results: Flavonoids from Z. clinopodioides (ZCF) were identified as the main components, with linarin being the most abundant. ZCF and linarin improved spatial memory, reduced Aβ deposition and Tau phosphorylation, and suppressed glial cell activation. Mechanistically, ZCF and linarin decreased NLRP3 protein levels and NF-κB phosphorylation, while enhancing LC3B, p62, and Cathepsin D expression, resulting in reduced IL-1β and IL-18 secretion in 3 × Tg mice, HT22 cells or BV2 cells—effects reversed by autophagy inhibition. ZCF promoted NLRP3 and p62 co-localization, leading to NLRP3 degradation via autophagy without affecting its mRNA levels. ZCF restores the autophagy-lysosome pathway and suppresses NLRP3 inflammasome activation, significantly improving cognitive dysfunction in 3 × Tg-AD mice, and highlighting ZCF or linarin as promising candidates for AD treatment.

Aim of the study: Gentiopicroside (GPS) was isolated from the traditional Chinese medicine Gentiana rigescens Franch, normally called as Long Dan. The anti-aging activity of GPS and the anti-AD effects of 2H-GPS, a reduced derivative of GPS have been reported previously. In this study, 2H-GPSE was designed to optimize the structure and improve its bioavailability and bioactivity.

Results: 2H-GPSE exerts its anti-AD effects through two different mechanisms. Western Blot, CETSA, DARTS and SPR were used to explore the targets of 2H-GPSE, and the results showed that 2H-GPSE directly targeted the α, β, and γ subunits of AMP-activated protein kinase (AMPK) and activated the AMPK-SIRT1-FoxO3A signaling pathway. And then, 16S rRNA gene amplicon sequencing analysis of fecal samples revealed that it acts on the brain-gut axis to regulate the levels of indole metabolites in the gut microbiota, including 3-indollepropionic acid (IPA), 3-indollemethanol (I3C), and 3-indoleacetic acid (3IA). In addition, Tau and Aβ proteins aggregates are characteristic of AD, and by visualizing and quantifying tau deposition and Aβ expression using PET and western blot, the results showed that 2H-GPSE was superior to donepezil (DON) for Tau and Aβ clearance.

Aim of the study: Succinate receptor 1 (SUCNR1) activation promotes microglial polarization, exacerbating Aβ deposition and neuroinflammation in Alzheimer's disease (AD). While Jiawei Xionggui decoction (JWXG), a traditional Chinese herbal formulation, demonstrates therapeutic potential by modulating microglial activity, its precise molecular mechanisms require further elucidation.

Results: JWXG treatment significantly improved cognitive function in APP/PS1 mice, enhancing working memory (Y-maze spontaneous alternation rate) and spatial learning/memory (Morris-water-maze performance), while attenuating neuronal loss and hippocampal degeneration. JWXG administration markedly reduced Aβ burden through enhanced microglial clearance, evidenced by decreased plaque deposition and increased Iba1+microglial clustering around deposits. Mechanistically, JWXG suppressed SUCNR1-mediated neuroinflammation by downregulating plaque-associated microglial SUCNR1 expression, inhibiting the succinate-MCT1 (monocarborxylat transporter 1)-SUCNR1 signaling cascade, and shifting microglial polarization from pro-inflammatory (CD86+, IL-1β+) to anti-inflammatory (CD206+, IL-10+) phenotypes.