Deletion of Dcf1 Reduces Amyloid-β Aggregation and Mitigates Memory Deficits

2021 ◽  
pp. 1-14
Author(s):  
Wei-hao Li ◽  
Lin-hua Gan ◽  
Fang-fang Ma ◽  
Rui-li Feng ◽  
Jiao Wang ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Senile Plaque ◽  
Uv Spectroscopy ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Aβ Aggregation ◽  
Climbing Ability ◽  
High Level ◽  
Development Methods

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-β (Aβ) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aβ aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. Objective: Our goal is to investigate the effect of Dcf1 on Aβ aggregation and memory deficits in AD development. Methods: The mouse and Drosophila AD model were used to test the expression and aggregation of Aβ, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. Results: Deletion of Dcf1 resulted in decreased Aβ42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aβ42 AD Drosophila, the expression of Dcf1 in Aβ42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aβ aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. Conclusion: Dcf1 causes Aβ-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.

Tph2 Genetic Ablation Contributes to Senile Plaque Load and Astrogliosis in APP/PS1 Mice

2019 ◽  
Vol 16 (3) ◽  
pp. 219-232 ◽  
Author(s):  
Chao-Jin Xu ◽  
Jun-Ling Wang ◽  
Jing-Pan ◽  
Min-Liao
Keyword(s):  
Congo Red ◽  
Tryptophan Hydroxylase ◽  
Senile Plaque ◽  
Senile Plaques ◽  
Critical Role ◽  
Amyloid Β ◽  
Conditional Knockout ◽  
Genetic Ablation ◽  
Congo Red Staining

Background: Amyloid-β (Aβ) accumulation plays a critical role in the pathogenesis of Alzheimer’s disease (AD) lesions. Deficiency of Serotonin signaling recently has been linked to the increased Aβ level in transgenic mice and humans. In addition, tryptophan hydroxylase-2 (Tph2), a second tryptophan hydroxylase isoform, controls brain serotonin synthesis. However, it remains to be determined that whether Tph2 deficient APP/PS1mice affect the formation of Aβ plaques in vivo. Methods: Both quantitative and qualitative immunochemistry methods, as well as Congo red staining were used to evaluate the Aβ load and astrogliosis in these animals. Results: we studied alterations of cortex and hippocampus in astrocytes and senile plaques by Tph2 conditional knockout (Tph2 CKO) AD mice from 6-10 months of age. Using Congo red staining and immunostained with Aβ antibody, we showed that plaques load or plaques numbers significantly increased in Tph2 CKO experimental groups at 8 to 10 months old, compared to wild type (WT) group, respectively. Using GFAP+ astrocytes immunofluorescence method, we found that the density of GFAP+ astrocytes markedly enhanced in Tph2 CKO at 10 months. We showed Aβ plaques co-localized autophagic markers LC3 and p62. Nevertheless, we did not observe any co-localization between GFAP+ astrocytes and autophagic markers, but detected the co-localization between βIII-tubulin+ neurons and autophagic markers. Conclusion: Overall, our work provides the preliminary evidence in vivo that Tph2 plays a role in amyloid plaques generation.

scholarly journals Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice

2007 ◽  
Vol 178 (5) ◽  
pp. 829-841 ◽  
Author(s):  
Ping He ◽  
Zhenyu Zhong ◽  
Kristina Lindholm ◽  
Lilian Berning ◽  
Wendy Lee ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Transgenic Mice ◽  
Learning And Memory ◽  
Tumor Necrosis ◽  
Death Receptor ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Plaque Formation ◽  
App Processing ◽  
Necrosis Factor

The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

scholarly journals Improvement of Learning and Memory Deficits With Aerobic Training and Donepezil Co-therapy in Amyloid-β beta-injected Male Rats Through the CREB and BDNF Signaling Pathway

2020 ◽  
Author(s):  
Iman Mohseni ◽  
Maghsoud Peeri ◽  
Mohammad Ali Azarbayjani
Keyword(s):  
Alzheimer Disease ◽  
Learning And Memory ◽  
Aerobic Training ◽  
Amyloid Β ◽  
Training Group ◽  
Memory Deficits ◽  
Drug Group ◽  
Male Rats ◽  
Control Group ◽  
Learning And Memory Deficits

Background: Accumulation of amyloid-β (Aß) plaques, primarily in the hippocampus, leads to neuronal death and Alzheimer disease. Exercise and medications can prevent and treat neuronal diseases. This study aimed to determine the effects of aerobic training and donepezil, a medication used in Alzheimer disease, on the improvement of learning and memory deficits in Aß-injected male rats. Objectives: This study aimed to determine the effects of aerobic training and donepezil, a medication used in Alzheimer disease, on the improvement of learning and memory deficits in Aß-injected male rats.Methods: Male Rats were injected with an Aβ solution into their CA1 hippocampal region. After 20 days, the rats were treated with donepezil hydrochloride at doses of 2 mg/kg/d by gavage and following treadmill exercise for 4 weeks. Then, after 24 h, they performed the Morris water maze test for five days. Additionally, we studied the molecular factors involved in neuronal plasticity, such as Ca2+/cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) on day 33. The animals were also evaluated histologically to determine the deposition of Aβ in the brain tissue. Results: Behavioral analysis showed that in the probe test, the latency to the platform zone significantly increased in the training group (F1,20=6.815; P<0.05) and in the drug group (F1,20=6.369; P<0.05). But there were no significant changes in the combined group compared with the control group (F1,20=3.909; P>0.05). Molecular analysis showed that CREB gene expression improved in the training group (F1,8=9893.539; P<0.01) and in the drug group (F1,8=631.958; P<0.01). But in the combined group, there were no significant changes compared with the Aβ group (F1,8=2.556; P>0.05). BDNF gene expression improved in the training group (F1,8=25.077; P<0.001), and in the drug group (F1,8=45.296; P<0.001). Also, in the combined group, this change was significant compared with the control group (F1,8=64.342; P<0.001). Histomorphometric analysis showed that the density of survived neurons was considerably increased in the combined group (P<0.01), and the drug group (P<0.05) compared to the control group Conclusion: In the present study, behavioral and biochemical analysis demonstrated that aerobic training and donepezil hydrochloride treatment for 4 weeks protect Aβ-injected male rats against memory impairment.

Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer’s disease

2020 ◽  
Author(s):  
Naomi Nihonmatsu-Kikuchi ◽  
Xiu-Jun Yu ◽  
Yoshiki Matsuda ◽  
Nobuyuki Ozawa ◽  
Taeko Ito ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaque ◽  
Morphological Changes ◽  
Expression Profiles ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Culture Method ◽  
Adult Brain

AbstractThe roles played by oligodendrocyte (OL) lineage cells, the largest glial population in the adult CNS, in the pathogenesis of Alzheimer’s disease (AD) remain elusive. Here, we show a newly developed culture method for adult OL progenitor cells (aOPCs) and identify novel plexin-B3-expressing (plexin-B3+) aOPCs as potential amyloid β peptides (Aβ)-secreting cells. Fibroblast growth factor 2 (FGF2) promotes the survival and proliferation of aOPCs in a serum-free defined medium. Although the whole expression profiles of the expanded aOPCs closely resemble those of in vivo OPCs, we found a subpopulation (up to 5%) of plexin-B3+/olig2+ aOPCs in the cultures growing in FGF2. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs with increased APP expression, Aβ1-40, −42 secretions and Aβ1-42/total Aβ ratios in association with cored senile plaque-like morphological changes. In vivo, plexin-B3+ aOPCs are distributed throughout the adult brain, although less densely so than NG2+ aOPCs. Spreading depolarization, a type of brain injury, induced unique delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral, but not in the contralateral, remote cortex. In AD brains, virtually all senile plaques in the cortex were immunostained with plexin-B3 antibodies and the levels of cortical plexin-B3 expression increased significantly in the Salcosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs play important roles in the pathogenesis of AD most likely as a natural Aβ source.

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