Pub Date : 2025-09-01Epub Date: 2024-09-24DOI: 10.4103/NRR.NRR-D-24-00536
Victoria Jiménez Carretero, Iris Álvarez-Merz, Jorge Hernández-Campano, Sergei A Kirov, Jesús M Hernández-Guijo
The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.
兴奋性氨基酸谷氨酸和天冬氨酸在脑缺血和兴奋性毒性中的作用已得到充分证实。然而,非兴奋性氨基酸在中风或脑外伤后脑损伤中的作用在很大程度上仍未得到充分研究。缺血核心坏死细胞释放的氨基酸可能会导致半影扩大。我们的研究结果表明,当暴露于四种非兴奋性氨基酸(L-丙氨酸、甘氨酸、L-谷氨酰胺和 L-丝氨酸)的血浆浓度混合物时,瞬时缺氧引起的场兴奋性突触后电位的可逆性丧失变得不可逆。缺氧时,这些氨基酸会诱发神经元和星形胶质细胞的体细胞肿胀,并由 N-甲基-D-天冬氨酸受体介导造成永久性树突损伤。阻断 N-甲基-D-天冬氨酸受体可防止神经元在缺氧时因这些氨基酸的存在而受损。这些氨基酸通过丙氨酸-丝氨酸-半胱氨酸转运体 2 交换器和 N 系统转运体积聚引起的星形胶质细胞肿胀可能激活了体积调节阴离子通道,导致兴奋性毒素的释放,进而通过 N-甲基-D-天冬氨酸受体的激活造成神经元损伤。因此,以前未认识到的涉及非兴奋性氨基酸的机制可能会导致中风和创伤性脑损伤等神经系统急症中脑损伤的进展和扩大。了解这些途径可以突出减轻脑损伤的新治疗目标。
{"title":"Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage.","authors":"Victoria Jiménez Carretero, Iris Álvarez-Merz, Jorge Hernández-Campano, Sergei A Kirov, Jesús M Hernández-Guijo","doi":"10.4103/NRR.NRR-D-24-00536","DOIUrl":"10.4103/NRR.NRR-D-24-00536","url":null,"abstract":"<p><p>The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2024-06-03DOI: 10.4103/NRR.NRR-D-23-01348
Yi Wang, Yuning Li, Yakun Gu, Wei Ma, Yuying Guan, Mengyuan Guo, Qianqian Shao, Xunming Ji, Jia Liu
JOURNAL/nrgr/04.03/01300535-202509000-00022/figure1/v/2024-11-05T132919Z/r/image-tiff Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment of this condition. The aims of this study were to (1) determine the specific relationship between hypoxic and α-synuclein during the occur of poststroke cognitive impairment and (2) assess whether the serum phosphorylated α-synuclein level can be used as a biomarker for poststroke cognitive impairment. We found that the phosphorylated α-synuclein level was significantly increased and showed pathological aggregation around the cerebral infarct area in a mouse model of ischemic stroke. In addition, neuronal α-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia, suggesting that hypoxia is the underlying cause of α-synuclein-mediated pathology in the brains of mice with ischemic stroke. Serum phosphorylated α-synuclein levels in patients with ischemic stroke were significantly lower than those in healthy subjects, and were positively correlated with cognition levels in patients with ischemic stroke. Furthermore, a decrease in serum high-density lipoprotein levels in stroke patients was significantly correlated with a decrease in phosphorylated α-synuclein levels. Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury, some of them exhibited decreased cognitive function and reduced phosphorylated α-synuclein levels. Taken together, our results suggest that serum phosphorylated α-synuclein is a potential biomarker for poststroke cognitive impairment.
{"title":"Decreased levels of phosphorylated synuclein in plasma are correlated with poststroke cognitive impairment.","authors":"Yi Wang, Yuning Li, Yakun Gu, Wei Ma, Yuying Guan, Mengyuan Guo, Qianqian Shao, Xunming Ji, Jia Liu","doi":"10.4103/NRR.NRR-D-23-01348","DOIUrl":"10.4103/NRR.NRR-D-23-01348","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202509000-00022/figure1/v/2024-11-05T132919Z/r/image-tiff Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment of this condition. The aims of this study were to (1) determine the specific relationship between hypoxic and α-synuclein during the occur of poststroke cognitive impairment and (2) assess whether the serum phosphorylated α-synuclein level can be used as a biomarker for poststroke cognitive impairment. We found that the phosphorylated α-synuclein level was significantly increased and showed pathological aggregation around the cerebral infarct area in a mouse model of ischemic stroke. In addition, neuronal α-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia, suggesting that hypoxia is the underlying cause of α-synuclein-mediated pathology in the brains of mice with ischemic stroke. Serum phosphorylated α-synuclein levels in patients with ischemic stroke were significantly lower than those in healthy subjects, and were positively correlated with cognition levels in patients with ischemic stroke. Furthermore, a decrease in serum high-density lipoprotein levels in stroke patients was significantly correlated with a decrease in phosphorylated α-synuclein levels. Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury, some of them exhibited decreased cognitive function and reduced phosphorylated α-synuclein levels. Taken together, our results suggest that serum phosphorylated α-synuclein is a potential biomarker for poststroke cognitive impairment.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2024-06-19DOI: 10.4103/NRR.NRR-D-24-00157
Jangampalli Adi Pradeepkiran, Priyanka Rawat, Arubala P Reddy, Erika Orlov, P Hemachandra Reddy
JOURNAL/nrgr/04.03/01300535-202509000-00024/figure1/v/2024-11-05T132919Z/r/image-tiff The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are extensions of a neuron's cellular body that are used to start networks. Here we explored the effects of diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate (DDQ) on neurite developmental features in HT22 neuronal cells. In this work, we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22 cells expressing mutant Tau (mTau) cDNA. To investigate DDQ characteristics, cell viability, biochemical, molecular, western blotting, and immunocytochemistry were used. Neurite outgrowth is evaluated through the segmentation and measurement of neural processes. These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth. These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22. DDQ-treated mTau-HT22 cells (HT22 cells transfected with cDNA mutant Tau) were seen to display increased levels of synaptophysin, MAP-2, and β-tubulin. Additionally, we confirmed and noted reduced levels of both total and p-Tau, as well as elevated levels of microtubule-associated protein 2, β-tubulin, synaptophysin, vesicular acetylcholine transporter, and the mitochondrial biogenesis protein-peroxisome proliferator-activated receptor-gamma coactivator-1α. In mTau-expressed HT22 neurons, we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth. Our findings conclude that mTau-HT22 (Alzheimer's disease) cells treated with DDQ have functional neurite developmental characteristics. The key finding is that, in mTau-HT22 cells, DDQ preserves neuronal structure and may even enhance nerve development function with mTau inhibition.
{"title":"Small molecule inhibitor DDQ-treated hippocampal neuronal cells show improved neurite outgrowth and synaptic branching.","authors":"Jangampalli Adi Pradeepkiran, Priyanka Rawat, Arubala P Reddy, Erika Orlov, P Hemachandra Reddy","doi":"10.4103/NRR.NRR-D-24-00157","DOIUrl":"10.4103/NRR.NRR-D-24-00157","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202509000-00024/figure1/v/2024-11-05T132919Z/r/image-tiff The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are extensions of a neuron's cellular body that are used to start networks. Here we explored the effects of diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate (DDQ) on neurite developmental features in HT22 neuronal cells. In this work, we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22 cells expressing mutant Tau (mTau) cDNA. To investigate DDQ characteristics, cell viability, biochemical, molecular, western blotting, and immunocytochemistry were used. Neurite outgrowth is evaluated through the segmentation and measurement of neural processes. These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth. These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22. DDQ-treated mTau-HT22 cells (HT22 cells transfected with cDNA mutant Tau) were seen to display increased levels of synaptophysin, MAP-2, and β-tubulin. Additionally, we confirmed and noted reduced levels of both total and p-Tau, as well as elevated levels of microtubule-associated protein 2, β-tubulin, synaptophysin, vesicular acetylcholine transporter, and the mitochondrial biogenesis protein-peroxisome proliferator-activated receptor-gamma coactivator-1α. In mTau-expressed HT22 neurons, we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth. Our findings conclude that mTau-HT22 (Alzheimer's disease) cells treated with DDQ have functional neurite developmental characteristics. The key finding is that, in mTau-HT22 cells, DDQ preserves neuronal structure and may even enhance nerve development function with mTau inhibition.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2024-09-06DOI: 10.4103/NRR.NRR-D-24-00503
Andrew Gregory, Chengyun Tang, Fan Fan
{"title":"Soluble epoxide hydrolase: a next-generation drug target for Alzheimer's disease and related dementias.","authors":"Andrew Gregory, Chengyun Tang, Fan Fan","doi":"10.4103/NRR.NRR-D-24-00503","DOIUrl":"https://doi.org/10.4103/NRR.NRR-D-24-00503","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2024-09-06DOI: 10.4103/NRR.NRR-D-24-00355
Chonglin Su, Taiqi Huang, Meiyu Zhang, Yanyu Zhang, Yan Zeng, Xingxing Chen
The hypothalamic-pituitary-adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic-pituitary-adrenal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor-mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic-pituitary-adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment-associated diseases, such as Alzheimer's disease, aging, depression, Parkinson's disease, Huntington's disease, stroke, and addiction, often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic-pituitary-adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.
{"title":"Glucocorticoid receptor signaling in the brain and its involvement in cognitive function.","authors":"Chonglin Su, Taiqi Huang, Meiyu Zhang, Yanyu Zhang, Yan Zeng, Xingxing Chen","doi":"10.4103/NRR.NRR-D-24-00355","DOIUrl":"10.4103/NRR.NRR-D-24-00355","url":null,"abstract":"<p><p>The hypothalamic-pituitary-adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic-pituitary-adrenal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor-mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic-pituitary-adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment-associated diseases, such as Alzheimer's disease, aging, depression, Parkinson's disease, Huntington's disease, stroke, and addiction, often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic-pituitary-adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2024-09-24DOI: 10.4103/NRR.NRR-D-24-00476
Thu Nguyen Minh Pham, Christian Behl
{"title":"Cellular models of stress resistance may pave ways to fight neurodegenerative diseases.","authors":"Thu Nguyen Minh Pham, Christian Behl","doi":"10.4103/NRR.NRR-D-24-00476","DOIUrl":"https://doi.org/10.4103/NRR.NRR-D-24-00476","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><p>JOURNAL/nrgr/04.03/01300535-202509000-00031/figure1/v/2024-11-05T132919Z/r/image-tiff A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore,
{"title":"Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways.","authors":"Biao Xiao, Chaoyang Chu, Zhicheng Lin, Tianyuan Fang, Yuyu Zhou, Chuxia Zhang, Jianghui Shan, Shiyu Chen, Liping Li","doi":"10.4103/NRR.NRR-D-23-01681","DOIUrl":"10.4103/NRR.NRR-D-23-01681","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202509000-00031/figure1/v/2024-11-05T132919Z/r/image-tiff A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, ","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}