Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer’s disease

Dejakaisaya, Hattapark; Harutyunyan, Anna; Kwan, Patrick; Jones, Nigel C.

doi:10.1007/s11306-021-01793-4

Cited by 13 publications

(8 citation statements)

References 72 publications

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“…In total, eleven metabolic pathways with an impact score ≥0.1 were significantly altered in 5xFAD females compared to WT females while only two pathways were significantly altered in 5xFAD males compared to WT males. Notably , several of the pathways altered in 5xFAD females, including purine metabolism, pyrimidine metabolism, glycerophospholipid metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, are in agreement with findings from previous metabolomics studies in other mouse models of Aβ accumulation ( González-Domínguez et al, 2014 ; González-Domínguez et al, 2015 ; Dejakaisaya et al, 2021 ; Zhao et al, 2021 ).…”

Section: Discussionsupporting

confidence: 89%

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

et al. 2021

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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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Section: Discussionsupporting

confidence: 89%

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

et al. 2021

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“…Pyrimidine biosynthesis is necessary for the maintenance of fundamental cellular functions and occurs in the mitochondria ( Wang W. et al, 2021 ). Recently, researchers found pyrimidine metabolism disorder both in the cerebral cortex of Tg2576 mice ( Dejakaisaya et al, 2021 ) and in the urine of demented rats ( Huang et al, 2022 ), which, together with our findings, strongly suggests an association between pyrimidine metabolism and AD. In the present study, three differential metabolites were enriched in this pathway.…”

Section: Discussionsupporting

confidence: 86%

Gut microbiota may be involved in Alzheimer’s disease pathology by dysregulating pyrimidine metabolism in APP/PS1 mice

Feng

Hou²,

Zhou³

et al. 2022

Front. Aging Neurosci.

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IntroductionAlzheimer’s disease (AD) is the most common form of dementia worldwide. The biological mechanisms underlying the pathogenesis of AD aren’t completely clear. Studies have shown that the gut microbiota could be associated with AD pathogenesis; however, the pathways involved still need to be investigated.AimsTo explore the possible pathways of the involvement of gut microbiota in AD pathogenesis through metabolites and to identify new AD biomarkers.MethodsSeven-month-old APP/PS1 mice were used as AD models. The Morris water maze test was used to examine learning and memory ability. 16S rRNA gene sequencing and widely targeted metabolomics were used to identify the gut microbiota composition and fecal metabolic profile, respectively, followed by a combined analysis of microbiomics and metabolomics.ResultsImpaired learning abilities were observed in APP/PS1 mice. Statistically significant changes in the gut microbiota were detected, including a reduction in β-diversity, a higher ratio of Firmicutes/Bacteroidota, and multiple differential bacteria. Statistically significant changes in fecal metabolism were also detected, with 40 differential fecal metabolites and perturbations in the pyrimidine metabolism. Approximately 40% of the differential fecal metabolites were markedly associated with the gut microbiota, and the top two bacteria associated with the most differential metabolites were Bacillus firmus and Rikenella. Deoxycytidine, which causes changes in the pyrimidine metabolic pathway, was significantly correlated with Clostridium sp. Culture-27.ConclusionsGut microbiota may be involved in the pathological processes associated with cognitive impairment in AD by dysregulating pyrimidine metabolism. B. firmus, Rikenella, Clostridium sp. Culture-27, and deoxyuridine may be important biological markers for AD. Our findings provide new insights into the host-microbe crosstalk in AD pathology and contribute to the discovery of diagnostic markers and therapeutic targets for AD.

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“…The details are shown in Table 2. Similar to AD patients, the changes of PS in brains are also not consistent in different animal models of AD as shown in Table 3 (Yao et al, 2009;Gonzalez-Dominguez et al, 2014;Martinez-Gardeazabal et al, 2017;Fitzner et al, 2020;Yi et al, 2020;Dejakaisaya et al, 2021). The reasons for this inconsistency may be explained by brain regions, Braak stages, age in the AD patients, and different experimental methods in studies.…”

Section: Alzheimer's Diseasementioning

confidence: 98%

Phosphatidylserine, inflammation, and central nervous system diseases

Wang

et al. 2022

Front. Aging Neurosci.

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Phosphatidylserine (PS) is an anionic phospholipid in the eukaryotic membrane and is abundant in the brain. Accumulated studies have revealed that PS is involved in the multiple functions of the brain, such as activation of membrane signaling pathways, neuroinflammation, neurotransmission, and synaptic refinement. Those functions of PS are related to central nervous system (CNS) diseases. In this review, we discuss the metabolism of PS, the anti-inflammation function of PS in the brain; the alterations of PS in different CNS diseases, and the possibility of PS to serve as a therapeutic agent for diseases. Clinical studies have showed that PS has no side effects and is well tolerated. Therefore, PS and PS liposome could be a promising supplementation for these neurodegenerative and neurodevelopmental diseases.

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Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer’s disease

Cited by 13 publications

References 72 publications

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

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

Gut microbiota may be involved in Alzheimer’s disease pathology by dysregulating pyrimidine metabolism in APP/PS1 mice

Phosphatidylserine, inflammation, and central nervous system diseases

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