The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology impacts upon the metabolome is still not understood, nor is it known how disturbances change as the disease progresses. For the first time we have profiled longitudinally (6, 8, 10, 12 and 18 months) both the brain and plasma metabolome of APP/PS1 double transgenic and wild type (WT) mice. A total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished APP/PS1 from WT mice at 8, 10 and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched chain amino acids and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis was evident in two age groups. AD-like pathology therefore impacts greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.
Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10-16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.
We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer’s disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.
Brain is a lipid-rich tissue, and fatty acids (FAs) play a crucial role in brain function, including neuronal cell growth and development. This study used GC-MS to survey all detectable FAs in the human parietal cortex (Brodmann area 7). These FAs were accurately quantified in 27 cognitively normal age-matched controls, 16 cases of moderate Alzheimer’s disease (AD), 30 severe AD, and 14 dementia with Lewy bodies (DLB). A total of 24 FA species were identified. Multiple comparison procedures, using stepdown permutation tests, noted higher levels of 13 FAs but the majority of changes were in moderate AD and DLB, rather than severe AD. Subjects with moderate AD and DLB pathology exhibited significantly higher levels of a number of FAs (13 FAs and 12 FAs, respectively). These included nervonic, lignoceric, cis-13,16-docosadienoic, arachidonic, cis-11,14,17-eicosatrienoic, erucic, behenic, α-linolenic, stearic, oleic, cis-10-heptanoic, and palmitic acids. The similarities between moderate AD and DLB were quite striking—arachidic acid was the only FA which was higher in moderate AD than control, and was not similarly affected in DLB. Furthermore, there were no significant differences between moderate AD and DLB. The associations between each FA and a number of variables, including diagnosis, age, gender, Aβ plaque load, tau load, and frontal tissue pH, were also investigated. To conclude, the development of AD or DLB pathology affects brain FA composition but, intriguingly, moderate AD neuropathology impacts this to a much greater extent. Post-mortem delay is a potential confounding factor, but the findings here suggest that there could be a more dynamic metabolic response in the earlier stages of the disease pathology.
We examined the evidence for intermittent fasting (IF) as a preventative tool to influence β-amyloid in animal models of Alzheimer’s disease (AD). A Scopus, Ovid, PubMed, and Web of Science (WoS), search yielded 29 results using the keywords “amyloid beta”, “intermittent fasting”, “intermittent caloric restriction”, “alternate day fasting”, “modified alternate-day fasting”, “time-restricted feeding”, “Ramadan fast”, “intermittent calori* restriction”, “intermittent restrictive diet”, and “Alzheimer*”. Five research articles addressed directly the effects of intermittent fasting on β-amyloid levels in animal models of AD: alternate day fasting (ADF) and time-restricted feeding (TRF) methods were incorporated in these studies. The study designs were found to be heterogeneous. Variations in the levels of β-amyloid peptides or plaque in either the hippocampus, cortical areas, or both in animals following dietary intervention were observed as compared to the ad libitum group. Non-significant changes were observed in three studies, while two studies interestingly demonstrated amelioration and reduction in β-amyloid levels. Given the conflicting results obtained from this study, significant care has to be taken into consideration before the protocol can be applied as a preventative approach to treat Alzheimer’s disease. Longitudinal research is warranted to fully grasp how dietary habits can help alleviate the disease either through upstream or downstream of AD pathology.
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