Rapamycin and Alzheimer’s disease: Time for a clinical trial?
Kaeberlein M, Galvan V
Science Translational Medicine. 2019 Jan 23;11(476). pii: eaar4289. doi: 10.1126/scitranslmed.aar4289.
The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer’s disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer’s disease. We argue that such clinical trials should be undertaken.
Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans.
Aiping Xu, Zhao Zhang, Su‐Hyuk Ko, Alfred L. Fisher, Zhijie Liu, Lizhen Chen
Aging Cell. 14 January 2019. doi: 10.1111/acel.12884. [Epub ahead of print].
Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.
Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors.
Gao CZ, Dong W, Cui ZW, Yuan Q, Hu XM, Wu QM, Han X, Xu Y, Min ZL
Journal of Enzyme Inhibition and Medicinal Chemistry. 2019 Dec;34(1):150-162. doi: 10.1080/14756366.2018.1530224.
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-An emerging role for gut microbiome.
MahmoudianDehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G, Louie G, Kueider-Paisley A, Moseley MA, Thompson JW, St John Williams L, Tenenbaum JD, Blach C, Baillie R, Han X, Bhattacharyya S, Toledo JB, Schafferer S, Klein S, Koal T, Risacher SL, Kling MA, Motsinger-Reif A, Rotroff DM, Jack J, Hankemeier T, Bennett DA, De Jager PL, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, van Duijn CM, Saykin AJ, Kastenmüller G, Kaddurah-Daouk R; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.
Alzheimer’s & Dementia. 2019 Jan;15(1):76-92. doi: 10.1016/j.jalz.2018.07.217. Epub 2018 Oct 15.
INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer’s disease (AD).
METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.
RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.
DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
Effects of intravenous AICAR (5-aminoimidazole-4-carboximide riboside) administration on insulin signaling and resistance in premature baboons, Papio sp.
Blanco CL, Gastaldelli A, Anzueto DG, Winter LA, Seidner SR, McCurnin DC, Liang H, Javors MA, DeFronzo RA, Musi N
PLoS one. 2018 Dec 12;13(12):e0208757. doi: 10.1371/journal.pone.0208757. eCollection 2018.
Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5′ AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects.
Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure.
Wang C, Liu F, Frisch-Daiello JL, Martin S, Patterson TA, Gu Q, Liu S, Paule MG, Hanig JP, Slikker W Jr, Crawford PA, Wang C, Han X
Analytica Chimica Acta. 2018 Dec 11;1037:87-96. doi: 10.1016/j.aca.2017.11.052. Epub 2017 Nov 30.
Although numerous studies have raised public concerns regarding the safety of anesthetics including sevoflurane in children, the biochemical mechanisms leading to anesthetics-induced neurotoxicity remain elusive. Moreover, potential biomarker(s) for early detection of general anesthetics-induced brain injury are urgent for public health. We employed an enabling technology of shotgun lipidomics and analyzed nearly 20 classes and subclasses of lipids present in the blood serum of postnatal day (PND) 5 or 6 rhesus monkeys temporally collected after exposure to sevoflurane at a clinically relevant concentration or room-air as control. Lipidomics analysis revealed numerous significant anesthetic-induced changes of serum lipids and their metabolites as well as short chain acylcarnitines in the brain and cerebrospinal fluid after anesthetic exposure. These include decreased carnitine and acylcarnitines, unchanged triacylglycerol mass but accumulation of 16:0 and 18:1 fatty acyl chains in the triacylglycerol pool, losses of polyunsaturated fatty acids in both non-esterified fatty acid and phospholipid pools, and increased 4-hydroxynonenal content as early as 2 h after sevoflurane exposure. Importantly, the amounts of short chain acylcarnitines in the brain and cerebrospinal fluid were also significantly reduced after anesthetic exposure. We propose that this serum lipidomic profile can serve as indicative of neuronal damage. Our results reveal that sevoflurane exposure induces an energy deficient state in the brain evidenced by reduced free and acyl carnitine contents, as well as the presence of a pro-inflammatory state in the exposed animals, providing deep insights into the underlying mechanisms responsible for anesthetic-induced neurotoxicity.
Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.
Hulea L, Gravel SP, Morita M, Cargnello M, Uchenunu O, Im YK, Lehuédé C, Ma EH, Leibovitch M, McLaughlan S, Blouin MJ, Parisotto M, Papavasiliou V, Lavoie C, Larsson O, Ohh M, Ferreira T, Greenwood C, Bridon G, Avizonis D, Ferbeyre G, Siegel P, Jones RG, Muller W, Ursini-Siegel J, St-Pierre J, Pollak M, Topisirovic I
Cell Metabolism. 2018 Dec 4;28(6):817-832.e8. doi: 10.1016/j.cmet.2018.09.001.. Epub 2018 Sep 20.
There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.
Novel strategies for enhancing shotgun lipidomics for comprehensive analysis of cellular lipidomes.
Hu C, Wang C, He L, Han X
TrAC Trends in Analytical Chemistry. 2018 Nov 27. doi: doi.org/10.1016/j.trac.2018.11.028. [In press]
Shotgun lipidomics is one of the most powerful tools in analysis of cellular lipidomes in lipidomics, which directly analyzes lipids from lipid extracts of diverse biological samples with high accuracy/precision. However, despite its great advances in high throughput analysis of cellular lipidomes, low coverage of poorly ionized lipids, especially those species in very low abundance, and some types of isomers within complex lipid extracts by shotgun lipidomics remains a huge challenge. In the past few years, many strategies have been developed to enhance shotgun lipidomics for comprehensive analysis of lipid species. Chemical derivatization represents one of the most attractive and effective strategies, already receiving considerable attention. This review focuses on novel advanced derivatization strategies for enhancing shotgun lipidomics. It is anticipated that with the development of enhanced strategies, shotgun lipidomics can make greater contributions to biological and biomedical research.
NFκB Regulates Muscle Development and Mitochondrial Function.
Valentine JM, Li ME, Shoelson SE, Zhang N, Reddick RL, Musi N
J Gerontol A Biol Sci Med Sci. 2018 Nov 13. doi: 10.1093/gerona/gly262. [Epub ahead of print]
NFκB is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NFκB has been implicated in the regulation of metabolic processes and tissue mass; yet, its affects on mitochondrial function in this tissue are unclear. To investigate the role of NFκB on mitochondrial function and its relationship with muscle mass across the lifespan, we study a mouse model with muscle-specific NFκB suppression (MISR mice). In wild type mice there was a natural decline in muscle mass with aging that was accompanied by decreased mitochondrial function and mRNA expression of electron transport chain subunits. NFκB inactivation downregulated expression of PPARGC1A, while upregulating TFEB and PPARGC1B, as well as decreased gastrocnemius (but not soleus) muscle mass in early life (1-6 months old). Lower oxygen consumption rates occurred in gastrocnemius and soleus muscles from young MISR mice, whereas soleus (but not gastrocnemius) muscles from old MISR mice displayed increased oxygen consumption compared to age-matched controls. We conclude that the NFκB pathway plays an important role in muscle development and growth. The extent to which NFκB suppression alters mitochondrial function is age-dependent and muscle-specific. Lastly, mitochondrial function and muscle mass are tightly associated in both genotypes and across the lifespan.
Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
Cornelison GL, Levy SA, Jenson T, Frost B
Aging Cell. 2018 Nov 9:e12847. doi: 10.1111/acel.12847. [Epub ahead of print]
The nucleus is a spherical dual-membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer’s disease. While the presence of pore-lined, cytoplasm-filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau-induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau-induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies.