Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

Jung

et al. 2020

Sci Rep

Cerebrospinal fluid (CSF) Aβ42 and tau protein levels are established diagnostic biomarkers of Alzheimer's disease (AD). However, their inadequacy to represent clinical efficacy in drug trials indicates the need for new biomarkers. Sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based mass spectrometry (MS) is an advanced proteomic tool for large-scale, high-quality quantification. In this study, SWATH-MS showed that VGF, chromogranin-A, secretogranin-1, and opioid-binding protein/cell adhesion molecule were significantly decreased in 42 AD patients compared to 39 controls, whereas 14-3-3ζ was increased (FDR < 0.05). In addition, 16 other proteins showed substantial changes (FDR < 0.2). The expressions of the top 21 analytes were closely interconnected, but were poorly correlated with CSF Aβ42, tTau, and pTau181 levels. Logistic regression analysis and data mining were used to establish the best algorithm for AD, which created novel biomarker panels with high diagnostic value (AUC = 0.889 and 0.924) and a strong correlation with clinical severity (all p < 0.001). Targeted proteomics was used to validate their usefulness in a different cohort (n = 36) that included patients with other brain disorders (all p < 0.05). This study provides a list of proteins (and combinations thereof) that could serve as new AD biomarkers. Cerebrospinal fluid (CSF) levels of Aβ1-42 (Aβ42), total Tau (tTau), and phosphorylated Tau181 (pTau181) are diagnostic markers of Alzheimer's disease (AD) 1,2. These biomarkers are currently used to confirm the core pathology of AD, i.e., Aβ and tau pathology, in deceased patients while they are alive 3 , and are also monitored in AD therapeutic trials 4. However, accumulating evidence has demonstrated a lack of utility of these markers after clinical onset of AD due to early concentration plateaus 5 and poor reflection of the clinical benefits of therapeutics that target them 6. CSF proteins related to synaptic function, neurodegeneration, inflammation, and Aβ metabolism have recently been suggested as supplementary biomarkers 7 ; however, they have not yet been clinically adopted.

Section: Discussionsupporting

confidence: 87%

SWATH-MS analysis of cerebrospinal fluid to generate a robust battery of biomarkers for Alzheimer’s disease

Jung

et al. 2020

Sci Rep

“…Our findings advance the current understanding of FDG-PET changes in MCI, providing an explanatory model of FDG-PET hypermetabolism that has been observed in multiple studies in asymptomatic and symptomatic elderly subjects (for a review, see [28]). In line with our results, a recent study in MCI reported increased FDG-PET metabolism at low levels of amyloid-PET but not high levels of amyloid-PET [7].…”

Section: Discussionsupporting

confidence: 66%

FDG-PET hypermetabolism is associated with higher tau-PET in mild cognitive impairment at low amyloid-PET levels

et al. 2020

Background FDG-PET hypermetabolism can be observed in mild cognitive impairment (MCI), but the link to primary pathologies of Alzheimer’s diseases (AD) including amyloid and tau is unclear. Methods Using voxel-based regression, we assessed local interactions between amyloid- and tau-PET on spatially matched FDG-PET in 72 MCI patients. Control groups included cerebrospinal fluid biomarker characterized cognitively normal (CN, n = 70) and AD dementia subjects (n = 95). Results In MCI, significant amyloid-PET by tau-PET interactions were found in frontal, lateral temporal, and posterior parietal regions, where higher local tau-PET was associated with higher spatially corresponding FDG-PET at low levels of local amyloid-PET. FDG-PET in brain regions with a significant local amyloid- by tau-PET interaction was higher compared to that in CN and AD dementia and associated with lower episodic memory. Conclusion Higher tau-PET in the presence of low amyloid-PET is associated with abnormally increased glucose metabolism that is accompanied by episodic memory impairment.

“…We have recently suggested that microglia may represent a feasible target for early intervention in different neuroinflammatory conditions [32][33][34]. Importantly, melatonin was shown to inhibit microglial pro-inflammatory polarization in hypoxic conditions in animal models [35][36][37].…”

Section: Introductionmentioning

confidence: 99%

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

et al. 2020

Self Cite

Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin’s effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl2 (250 μM for 24 h). Melatonin (1 μM) significantly attenuated CoCl2 toxicity on microglia, an effect prevented by selective SIRT1 inhibitor EX527 (5 μM) and AMP-activated protein kinase (AMPK) inhibitor BML-275 (2 μM). CoCl2 did not modify SIRT1 expression, but prevented nuclear localization, while melatonin appeared to restore it. CoCl2 induced nuclear localization of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-kB), an effect contrasted by melatonin in an EX527-dependent fashion. Treatment of microglia with melatonin attenuated potentiation of neurotoxicity. Common carotid occlusion was performed in p7 rats, followed by intraperitoneal injection of melatonin (10 mg/kg). After 24 h, the number of Iba1+ microglia in the hippocampus of hypoxic rats was significantly increased, an effect not prevented by melatonin. At this time, SIRT1 was only detectable in the amoeboid, Iba1+ microglial population selectively localized in the corpus callosum. In these cells, nuclear localization of SIRT1 was significantly lower in hypoxic animals, an effect prevented by melatonin. NF-kB showed an opposite expression pattern, where nuclear localization in Iba1+ cells was significantly higher in hypoxic, but not in melatonin-treated animals. Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage.