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With an increase in aging populations worldwide, age-related diseases such as Alzheimer's disease (AD) have become a global concern. At present, a cure for neurodegenerative disease is lacking. There is an urgent need for a biomarker that can facilitate the diagnosis, classification, prognosis, and treatment response of AD. The recent emergence of highly sensitive mass-spectrometry platforms and high-throughput technology can be employed to discover and catalog vast datasets of small metabolites, which respond to changed status in the body. Metabolomics analysis provides hope for a better understanding of AD as well as the subsequent identification and analysis of metabolites. Here, we review the state-of-the-art emerging candidate biomarkers for AD. [ABSTRACT FROM AUTHOR]

A UPLC-Q-TOF/MS-based metabolomics study was carried out to explore the intervening mechanism of Corallodiscus flabellatus (Craib) B. L. Burtt (CF) extract on Alzheimer's disease (AD). The AD model group consisted of senescence-accelerated mouse prone 8 (SAMP8) mice, and the control group consisted of senescence-accelerated mouse resistant 1 (SAMR1) mice. UPLC-Q-TOF/MS detection, multivariate statistical analysis, and pathway enrichment were jointly performed to research the change in metabolite profiling in the urine of AD mice. The result suggested that the metabolite profiling of SAMP8 mice significantly changed at the sixth month compared with SAMR1 mice of the same age, and the principal component analysis (PCA) score scatter plots of the CF group closely resembled those of the control and positive drug (huperzine A, HA) group. A total of 28 metabolites were considered potential biomarkers associated with the metabolism of beta-alanine, glycine, serine, threonine, cysteine, methionine, arginine, proline, and purines in AD mice. Furthermore, the CF group was clustered with the control and positive group and was clearly separated from the model group in the heat map. In conclusion, significant anti-AD effects were firstly observed in mice after treatment with the CF extract, and the urinary metabolomics approach assisted with dissecting the underlying mechanism. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer's disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer's disease (AD), inhibiting amyloid-β (Aβ) production and promoting Aβ clearance. Advanced glycation end products (AGEs) promote Aβ aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aβ production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aβ pathology via inhibiting mTOR signaling.Objective: To explore whether BBR ameliorates ribosylation-induced Aβ pathology in APP/PS1 mice.Methods: Western blot and immunofluorescence staining were used to detect the related proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aβ generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aβ42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice.Results: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aβ-degrading enzymes and Neprilysin, and inhibits the expression of Aβ in APP/PS1 mice.Conclusion: BBR ameliorates ribosylation-induced Aβ pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and currently there is no effective cure for this devastating disease. Decreases in the levels of β 2 -adrenoceptor (β 2 -AR) and norepinephrine have been reported in several regions of AD brains. The activation of β 2 AR can prevent the amyloid β (Aβ)-mediated inhibition of LTP (Long-term potentiation), but the mechanism is not fully understood. Here, we used APP/PS1 mice to study whether the activation of β 2 AR could remodel synaptic and/or dendritic plasticity. We found that the activation of β 2 AR by Clenbuterol (Clen) ameliorated memory deficits and promoted dendrite ramification and spine generation in hippocampal CA1 neurons, which was accompanied by the upregulation of postsynaptic density protein 95 (PSD95), synapsin 1 and synaptophysin. Conversely, the inhibition of β 2 AR by a siRNA blocked the Clen-induced increase in dendrite ramification and dendritic spines in primary hippocampal neurons. Furthermore, the activation of β 2 AR decreased cerebral amyloid plaques through the up-regulation of α-secretase activity and by decreasing the phosphorylation of APP at Thr668. Based on the roles of β 2 AR in dendrite ramification and spine generation, memory deficits and AD pathogenesis, compounds designed to activate β 2 AR might shed light on the cure of AD. [ABSTRACT FROM AUTHOR]