Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer’s Disease male mice

Xiao, Lan; Yang, Xiaoling; Sharma, Vinay; Abebe, Daniel; Loh, Y. Peng

doi:10.1038/s41380-023-02135-7

Cited by 6 publications

(1 citation statement)

References 62 publications

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“…The amyloid-beta 1-42 (Aβ1-42) peptide is a primary component of the amyloid plaques found in the brains of individuals with AD. It is believed to play a critical role in the neuropathology of AD by initiating a cascade of events that leads to neuronal dysfunction and death[ 3 ]. Memory loss and cognitive decline are caused by the buildup of Aβ plaques, neurofibrillary tangles, and synaptic and neuronal loss in individuals with AD[ 4 - 6 ].…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA improves Alzheimer’s disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

Yang,

Luo,

2024

World J Psychiatry

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BACKGROUND Alzheimer’s disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear. AIM To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms. METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction. RESULTS In vivo , Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling. CONCLUSION This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.

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Section: Introductionmentioning

confidence: 99%

Tanshinone IIA improves Alzheimer’s disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

Yang,

Luo,

2024

World J Psychiatry

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Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Jiang,

Liu,

et al. 2024

Transl Neurodegener

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Background Adult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD). Methods In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation. Results Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice. Conclusions CPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.

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Association Between Urinary Glyphosate Exposure and Cognitive Impairment in Older Adults from NHANES 2013-2014

Ren,

Yu,

Wang

et al. 2024

JAD

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Background: Glyphosate is the most commonly used herbicide with potential neurotoxicity. However, limited epidemical evidence is found in the relationship between glyphosate and cognitive impairment, especially in the cognitive-disrupting sensitive elderly populations. Objective: This study aimed to examine the association of urinary glyphosate exposure with cognitive impairment in the United State (US) older adults. Methods: Cognitive impairment was determined by the following four tests: the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Immediate Recall test (IR), the CERAD Delayed Recall tests (DR), the Animal Fluency (AF) test and the Digit Substitution test (DSST). Survey weighted logistic regression and restricted cubic splines were applied to evaluate and visualize the association between glyphosate and cognitive impairment. Results: A total of 465 elderly adults were identified in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle, and among them, 83.87% individuals had detectable urinary levels of glyphosate (0.628 ng/mL in average). After adjusting for the potential covariates, glyphosate was significantly linked to increased DR and AF impairment, and the corresponding ORs were 1.52 (1.01 to 2.30, p = 0.049) and 1.69 (1.11 to 2.59, p = 0.019), respectively. No significant association was identified between glyphosate and IR or DSST impairment. The RCS plot further confirmed the linear and positive relationships between glyphosate and DR and AF impairment. Conclusions: These findings suggested that exposure to glyphosate might be associated with declined cognitive function in the elderly, and it might be prudent to evaluate cognitive outcomes for aged individuals with glyphosate exposures.

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Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer’s Disease male mice

Cited by 6 publications

References 62 publications

Tanshinone IIA improves Alzheimer’s disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

Tanshinone IIA improves Alzheimer’s disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Association Between Urinary Glyphosate Exposure and Cognitive Impairment in Older Adults from NHANES 2013-2014

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