Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer’s amyloidosis model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE203554 | GEO | 2022/05/25
REPOSITORIES: GEO
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Project description:Neural stem cells residing in the hippocampal neurogenic niche sustain life-long neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer’s disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous pro-neurogenic effects in the adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly impacted by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic significance of targeting miR-132 in neurodegeneration.
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Project description:Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether modulating AHN is sufficient to improve these cognitive and noncognitive symptoms in AD remains elusive. Here we report that chronic stimulation of hypothalamic supramammillary nucleus (SuM) during early AD restores AHN in an otherwise impaired neurogenic niche. Strikingly, activation of SuM-enhanced adult-born neurons (ABNs) is sufficient to restore memory and emotion deficits in 5×FAD mice. Interestingly, activation of SuM-enhanced ABNs in AD mice increases CA3 and CA1 activity. To probe ABN-activity-dependent changes, we performed quantitative phosphoproteomics and found activation of SuM-enhanced ABNs promotes activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis. Functional assays further confirm increased CA1 long-term potentiation and enhanced microglia phagocytosis of plaques upon activation of SuM-enhanced ABNs. Our findings reveal a robust AHN-promoting strategy that is sufficient to restore AD-associated deficits and highlight ABN-activity-dependent mechanisms underlying functional improvement in AD.
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Project description:Mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance hippocampal function, while intense exercise (IE) above the LT negates such benefits. However, the question as to why ME more effectively enhances hippocampal function than does IE remains to be clarified. Here, we investigated adult hippocampal neurogenesis (AHN) as a mechanism of ME-induced cognitive improvement, and comprehensively delineated the transcriptomic profile of the hippocampus, using a rat whole-genome microarray approach through comparison with IE. Immunohistochemical results showed that less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 44 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF1), probably due to the timing of hippocampal tissue collection after the last training session and the technical feature of microarray. Rather, network analysis of the microarray data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with hippocampal neuroadaptations including AHN. In contrast, IE-influenced genes linked to immune response, a negative regulatory system of AHN and hippocampal function, were identified. Collectively, these results support our hypothesis that AHN could explain why ME enhances hippocampal function, and provide the ME-specific gene list that contain some potential regulators of this positive regulation. The list will become a foundation to elucidate the molecular pathway involving the ME-induced cognitive gain.
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Project description:Skeletal muscle adapts to exercise training of various modes, intensities and durations with a programmed gene expression response. This study dissects the independent and combined effects of exercise mode, intensity and duration to identify which exercise has the most positive effects on skeletal muscle health. Full details on exercise groups can be found in: Kraus et al Med Sci Sports Exerc. 2001 Oct;33(10):1774-84 and Bateman et al Am J Cardiol. 2011 Sep 15;108(6):838-44.
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Project description:Although clinically, Alzheimer's disease (AD) and vascular dementia (VaD) are considered two different types of dementia, it is unclear whether the cellular and molecular mechanisms of cognitive impairment related to these diseases have common features. Here, by using an ultraweak biophoton imaging system (UBIS) and synaptosomes isolated from early AD and VaD models, we found that biophotonic activity induced by glutamate was significantly decreased and blueshifted due to glutamate aggregation at synapses and changes in GluN2B-containing N-methyl-D-aspartate receptor (NMDAR) expression. Such changes could be partially reversed by ifenprodil, a specific antagonist of the GluN2B subunit of NMDAR. Additionally, the expression of BDNF, mTOR and Arc was decreased, while the expression of caspase3 was increased in synaptosomes from AD and VaD models. These findings suggest that in AD and VaD pathology, synaptic dysfunction is not only related to abnormal signal transmission but also associated with alterations in neuronal survival-death signals in synaptosomes, implying that AD and VaD may involve similar but complex changes in synaptic function and structure and the expression of related signalling molecules, which need to be further studied.
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Project description:Skeletal muscle adapts to exercise training of various modes, intensities and durations with a programmed gene expression response. This study dissects the independent and combined effects of exercise mode, intensity and duration to identify which exercise has the most positive effects on skeletal muscle health. Full details on exercise groups can be found in: Kraus et al Med Sci Sports Exerc. 2001 Oct;33(10):1774-84 and Bateman et al Am J Cardiol. 2011 Sep 15;108(6):838-44. This study uses a middle aged group of subjects that have 3+ markers of metabolic syndrome. One group remains an inactive control, while 5 groups undergo 9 mo supervised exercise training. Exercise groups are as follows: Inactive control (group B); Mild aerobic exercise - low amount/mod intensity (group A); Moderate aerobic exercise - low amt/vig intensity (group D); High aerobic exercise - high amt/vig intensity (group C); resistance training only (group F); and mod aerobic + resistance training (group E). Each group has 10 subjects (5 men and 5 women), however 3 subjects failed array QC, leaving 8 subjects in group E and 9 subjects in group F. Data were all analyzed pre to post training in a RM ANCOVA, covaried for age and sex or regression to determine genotype/phenotype interactions.
2015-05-14 | E-GEOD-48278 | biostudies-arrayexpress
Project description:Many studies have reported on beneficial aspects of running to improve hippocampus-related spatial memory and promote neuroplastic changes like adult hippocampal neurogenesis (AHN). Such research has also revealed molecular factors associated with molecular signaling by BDNF and IGF-I leading to CREB activation. However, the optimum exercise intensity for genome-wide beneficial effects remains unclear. We thus investigate the whole spectrum of hippocampal molecular change by exercise using DNA microarray-based transcript profiling in two different intensity groups. Lactate threshold (LT), at which lactate starts to accumulate in the blood, defined the intensity: mild- (ME, <LT) or intense-exercise (IE, >LT). Rats were subjected to 6 weeks of training or sedentary (CONT) regimes. After 6 weeks, spatial memory using Morris Water Maze (MWM), AHN, and hippocampal gene expressions were assessed. The functional relationships among the differentially expressed genes were generated using Ingenuity Pathway Analysis and QIAGEN-based pathway analysis. Results revealed that ME, but not IE, improved the performance on probe trial in MWM and increased newborn mature neurons (BrdU+/NeuN+ cells) compared with CONT. Transcript profiling by comparison with CONT postulated that ME regulated protein synthesis through IRS-dependent pathway (e.g. PI3K-Akt signaling cascade), cholesterol trafficking and perisynaptic environment, while IE induced dysfunction of these process and cell death. The comparison of the expression between each intensity also supported these tendencies. Collectively, our findings indicate mild exercise should be beneficial in the development of both enhanced AHN and spatial memory, and several genes related to protein synthesis and lipid-metabolism may be critical those neuroplastic changes. This study is the first step to identify the potential triggers of exercise-induced cognitive gain. Eleven-week-old male Wistar rats (220-270 g; SLC, Saitama, Japan) were housed in polycarbonate steel cages with a 12-h light/dark schedule (lights on at 7:00 a.m.) and given ad libitum access to food and water. A total of 98 rats were used in this study to assess the influence of exercise intensity on physiological states (training effect of skeletal muscle and stress level) (n= 22), MWM (n= 32), AHN (n= 22), and global gene expression profiles of hippocampal by microarray (n= 22). All animal care and experimental procedures were performed in accordance with protocols approved by the University of Tsukuba Animal Experiment Committee, based on the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (NIH publication, revised 1996). All efforts were made to minimize animal suffering and to reduce the number of animals used in this study. To adapt the rearing environment and remove any unintended stress effects, animals underwent a week of preliminary rearing to ambient conditions in groups housing conditions (2-3 rats/cage). After the preliminary rearing, the animals were randomized into three groups based on the LT of treadmill running: Sedentary control (CONT, rest on treadmill), Mild Exercise (ME, below LT, 15 m/min) or Intense Exercise (IE, above LT, 40 m/min). Exercise group was habituated to run on a treadmill (KN-73, Natsume Ltd., Tokyo, Japan) for 1 (for ME) or 4 (for IE) weeks. Within a given test period, rats were able to run on the above-mentioned running speeds. After this running habituation, rats were entered into the exercise training session for 6 weeks in total. The running duration was 60 min/day and frequency was 5 times/week. Exercise training was performed between 19:00 and 22:00 (during dark phase). Rat’s body weight and physical condition were monitored until the end of training. If rats could not perform well running on each determined speed and showed poor health, those were eliminated from the study. Based on the criteria, a total of 13 rats were eliminated (bad runner - 4 rats; poor health - 7 rats). Twenty-four or thirty-six hours after the last training, rats were processed to the next step. In the microarray group, the whole brain of each animal was rapidly removed, and hippocampus was separated on ice according to the method of Glowinski and Iversen (1966), with minor modifications. Hippocampi were immediately flash-frozen in liquid nitrogen. The deep-frozen hippocampi were transferred to a pre-chilled (in liquid nitrogen) mortar and pestle, and ground to a very fine powder with liquid nitrogen. The powdered samples were stored in aliquots at -80ºC till used for further analysis. Total RNA was extracted from each sample powder (~50 mg) using the QIAGEN RNeasy Mini Kit (QIAGEN, Maryland, USA). To verify the quality of this RNA, the yield and purity were determined spectrophotometrically (NanoPhotomaterTM, IMPLEN, Munich, Germany) and visually confirmed using formaldehyde gel electrophoresis. We used the sample with a ratio of spectrophotometric absorbance at 260 nm to that at 230 (A260/A230) or 280 nm (A260/A280) above 1.8. An equal amount of RNA (1000 ng) from the five rats, randomly picked up from each exercise group (n = 5), was pooled and used for microarray analysis. In this study, we performed three combinations of comparison analysis of gene expression change. First, we compared the difference between CONT and ME (combination 1) or IE (combination 2) to confirm the exercise-intensity-dependent gene expression change. Subsequently, we made a comparison of ME with IE (combination 3) to elucidate a ME-based difference of IE inducible gene. In all combinations, total RNA (1000 ng) was labeled with either Cy3 or Cy5 dye using an Agilent Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies Inc., CA, USA). Fluorescently labeled targets of control as well as treated samples were hybridized to the same microarray slide with 60-mer probes (4 x 44K (41,090 gene probes), rat whole genome, Agilent). A flip labelling (dye-swap or reverse labelling with Cy3 and Cy5 dyes) procedure was followed to nullify the dye bias associated with unequal incorporation of the two Cy dyes into cDNA. Hybridization and wash processes were performed according to the manufacturer’s instructions, and hybridized microarrays were scanned using an Agilent Microarray scanner. For the detection of significantly differentially expressed genes between control and exercise samples each slide image was processed by Agilent Feature Extraction software (version 9.5.3.1).
2014-04-05 | E-GEOD-45813 | biostudies-arrayexpress