CircTulp4 functions in Alzheimer’s disease pathogenesis by regulating its parental gene, Tulp4

AbstractAlzheimer’s disease (AD)—one of the most common neurodegenerative diseases worldwide—impairs cognition, memory, and language ability and causes dementia. However, AD pathogenesis remains poorly elucidated. Recently, a potential link between AD and circular RNAs (circRNAs) has been uncovered, but only a few circRNAs that might be involved in AD have been identified. Here, we systematically investigated circRNAs in the APP/PS1 model mouse brain through deep RNA-sequencing. We report that circRNAs are markedly enriched in the brain and that several circRNAs exhibit differential expression between wild-type and APP/PS1 mice. We characterized one abundant circRNA, circTulp4, derived from Intron1 of the gene Tulp4. Our results indicate that circTulp4 predominantly localizes in the nucleus and interacts with U1 snRNP and RNA polymerase II to modulate the transcription of its parental gene, Tulp4, and thereby regulate the function of the nervous system and might participate in the development of AD.

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The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

10.5327/1516-3180.280 ◽

2021 ◽

Author(s):

Fábio Dias Nogueira ◽

Ana Klara Rodrigues Alves ◽

Barbara Beatriz Lira da Silva ◽

Ana Kamila Rodrigues Alves ◽

Marlilia Moura Coelho Sousa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Potential Link ◽

The Central Nervous System ◽

Gsk 3Β ◽

Type 3 ◽

The Brain

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

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Withania somnifera showed neuroprotective effect and increase longevity in Drosophila Alzheimer’s disease model

10.1101/2020.04.27.063107 ◽

2020 ◽

Author(s):

Mardani Abdul Halim ◽

Izzah Madihah Rosli ◽

Siti Shafika Muhamad Jaafar ◽

Hoi-Min Ooi ◽

Pui-Wei Leong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Withania Somnifera ◽

Neuroprotective Effect ◽

Disease Model ◽

Ayurvedic Medicine ◽

Wild Type ◽

Potent Drug ◽

The Brain

AbstractAlzheimer’s disease is a complex neurodegenerative disease and is only unique to human. The disease is defined in human brain by the accumulation of amyloid beta in the parenchyma of the brain. Withania somnifera, commonly known as Ashwagandha is an Indian Ayurvedic medicine that has been used for centuries to treat countless range of human health problem. The active compound of Ashwagandha was shown to be beneficial in treating many neurodegenerative diseases including Alzheimer’s disease (AD). In this study, Drosophila melanogaster AD model was used to study the effect of Ashwagandha on the toxicity of beta amyloid and also the longevity effect of the compound. We found that 20 mg/mL of Ashwagandha was shown to be effective in rescuing the “rough eye phenotype” of AD Drosophila. Furthermore, Ashwagandha also promotes longevity in AD as well as wild-type Drosophila. The results above showed that Ashwagandha could potentially be a potent drug to treat AD as well as maintaining the wellbeing of cells.

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Abca7 deletion does not affect adult neurogenesis in the mouse

Bioscience Reports ◽

10.1042/bsr20150308 ◽

2016 ◽

Vol 36 (2) ◽

Cited By ~ 2

Author(s):

Hongyun Li ◽

Tim Karl ◽

Brett Garner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Abc Transporters ◽

Atp Binding ◽

Wild Type ◽

Atp Binding Cassette Transporter ◽

The Brain ◽

Deficient Mice ◽

Atp Binding Cassette

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and linked with Alzheimer's disease. Since other ABC transporters regulate adult neurogenesis, we assessed neurogenesis in wild-type (WT) and Abca7 deficient mice. Abca7 deletion did not affect adult neurogenesis in the mouse.

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Cognitive Function Improvement in Mouse Model of Alzheimer’s Disease Following Transcranial Direct Current Stimulation

Brain Sciences ◽

10.3390/brainsci10080547 ◽

2020 ◽

Vol 10 (8) ◽

pp. 547

Author(s):

Wang-In Kim ◽

Jae-Young Han ◽

Min-Keun Song ◽

Hyeng-Kyu Park ◽

Jihoon Jo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Mouse Model ◽

Direct Current ◽

Transcranial Direct Current Stimulation ◽

Wild Type ◽

Direct Current Stimulation ◽

Induction Group ◽

The Brain

Anodal transcranial direct current stimulation (tDCS) is a painless noninvasive method that reportedly improves cognitive function in Alzheimer’s disease (AD) by stimulating the brain. However, its underlying mechanism remains unclear. Thus, the present study investigates the cognitive effects in a 5xFAD AD mouse model using electrophysiological and pathological methods. We used male 5xFAD C57BL/6J and male C57BL/6J wild-type mice; the dementia model was confirmed through DNA sequencing. The verified AD and wild-type mice were randomly assigned into four groups of five mice each: an induced AD group receiving tDCS treatment (Stim-AD), an induced AD group not receiving tDCS (noStim-AD), a non-induction group receiving tDCS (Stim-WT), and a non-induction group not receiving tDCS (noStim-WT). In the Stim group, mice received tDCS in the frontal bregma areas at an intensity of 200 µA for 20 min. After 2 weeks of treatment, we decapitated the mice, removed the hippocampus from the brain, confirmed its neuronal activation through excitatory postsynaptic potential (EPSP) recording, and performed molecular experiments on the remaining tissue using western blots. EPSP significantly increased in the Stim-AD group compared to that in the noStim-AD, which was comparable to that in the non-induced groups, Stim-WT and noStim-WT. There were no significant differences in cyclic amp-response element binding protein (CREB), phosphorylated CREB (pCREB), and Brain-derived neurotrophic factor (BDNF) levels in the Stim-AD group compared to those in the noStim-AD group. This study demonstrated that a tDCS in both frontal lobes of a transgenic 5xFAD mouse model affects long-term potentiation, indicating possible enhancement of cognitive function.

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Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.788312 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alex B. Speers ◽

Manuel García-Jaramillo ◽

Alicia Feryn ◽

Donald G. Matthews ◽

Talia Lichtenberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Pathways ◽

Centella Asiatica ◽

Metabolomic Analysis ◽

Wild Type ◽

Amyloid Accumulation ◽

5Xfad Mouse ◽

5Xfad Mice ◽

The Brain

Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.

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Gut Inflammation Induced by Dextran Sulfate Sodium Exacerbates Amyloid-β Plaque Deposition in the App NL – G – F Mouse Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201099 ◽

2021 ◽

pp. 1-20

Author(s):

Mona Sohrabi ◽

Heidi L. Pecoraro ◽

Colin K. Combs

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Wild Type ◽

Gut Inflammation ◽

Plaque Deposition ◽

Brain Changes ◽

The Brain

Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and App NL - G - F mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and App NL - G - F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ 1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated App NL - G - F mice compared to vehicle treated App NL - G - F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system.

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Elevated Testosterone Level and Urine Scent Marking in Male 5xFAD Alzheimer Model Mice

Current Alzheimer Research ◽

10.2174/1567205017666200217105537 ◽

2020 ◽

Vol 17 (1) ◽

pp. 80-92 ◽

Cited By ~ 2

Author(s):

Lisa Gadomsky ◽

Malena dos Santos Guilherme ◽

Jakob Winkler ◽

Michael A. van der Kooij ◽

Tobias Hartmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sexual Behavior ◽

Mouse Model ◽

Cell Attachment ◽

Scent Marking ◽

Biochemical Properties ◽

Wild Type ◽

Testosterone Levels ◽

The Brain

Background: Function of the Amyloid Precursor Protein (AβPP) and its various cleavage products still is not unraveled down to the last detail. While its role as a source of the neurotoxic Amyloid beta (Aβ) peptides in Alzheimer’s Disease (AD) is undisputed and its property as a cell attachment protein is intriguing, while functions outside the neuronal context are scarcely investigated. This is particularly noteworthy because AβPP has a ubiquitous expression profile and its longer isoforms, AβPP750 and 770, are found in various tissues outside the brain and in non-neuronal cells. Objective: Here, we aimed at analyzing the 5xFAD Alzheimer’s disease mouse model in regard to male sexual function. The transgenes of this mouse model are regulated by Thy1 promoter activity and Thy1 is expressed in testes, e.g. by Sertoli cells. This allows speculation about an influence on sexual behavior. Methods: We analyzed morphological as well as biochemical properties of testicular tissue from 5xFAD mice and wild type littermates and testosterone levels in serum, testes and the brain. Sexual behavior was assessed by a urine scent marking test at different ages for both groups. Results: While sperm number, testes weight and morphological phenotypes of sperms were nearly indistinguishable from those of wild type littermates, testicular testosterone levels were significantly increased in the AD model mice. This was accompanied by elevated and prolonged sexual interest as displayed within the urine scent marking test. Conclusion: We suggest that overexpression of AβPP, which mostly is used to mimic AD in model mice, also affects male sexual behavior as assessed additional by the Urine Scent Marking (USM) test. The elevated testosterone levels might have an additional impact on central nervous system androgen receptors and also have to be considered when assessing learning and memory capabilities.

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Altered Brain Adiponectin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph13070150 ◽

2020 ◽

Vol 13 (7) ◽

pp. 150 ◽

Cited By ~ 1

Author(s):

Anishchal A. Pratap ◽

R. M. Damian Holsinger

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Receptor Expression ◽

Wild Type ◽

Model Of Alzheimer’S Disease ◽

Activated State ◽

5Xfad Mouse ◽

Neuronal Expression ◽

The Brain

Metabolic syndromes share common pathologies with Alzheimer’s disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer’s, we examined their expression in the aged 5XFAD mouse model of AD. In age-matched wild-type mice, we observed neuronal expression of both ARs throughout the brain as well as endothelial expression of AdipoR1. The pattern of receptor expression in the aged 5XFAD brain was significantly perturbed. Here, we observed decreased neuronal expression of both ARs and decreased endothelial expression of AdipoR1, but robust expression of AdipoR2 in activated astrocytes. We also observed AdipoR2-expressing astrocytes in the dorsomedial hypothalamic and thalamic mediodorsal nuclei, suggesting the possibility that astrocytes utilise AdipoR2 signalling to fuel their activated state in the AD brain. These findings provide further evidence of a metabolic disturbance and demonstrate a potential shift in energy utilisation in the AD brain, supporting imaging studies performed in AD patients.

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Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽

10.1024/1662-9647/a000074 ◽

2012 ◽

Vol 25 (4) ◽

pp. 235-245 ◽

Cited By ~ 64

Author(s):

Katja Franke ◽

Christian Gaser

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Brain Aging ◽

Elderly Subjects ◽

Additional Increase ◽

Longitudinal Changes ◽

Novel Method ◽

The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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