eRapport

Turning up NAD+-induced mitophagy to treat Alzheimer’s disease

Prosjekt
Prosjektnummer
2020001
Ansvarlig person
Evandro Fei Fang
Institusjon
Akershus universitetssykehus HF
Prosjektkategori
Åpen prosjektstøtte
Helsekategori
Neurological
Forskningsaktivitet
3. Prevention, 5. Treatment Developement
Rapporter
2024 - sluttrapport
Over the past 5 years, even with the challanges rasied by the COVID-10 pandemic, we performed all the experiments as we proposed and finisehd this project. 1. Over 20 papers, including directly and indirectly, related to this grant were published in leading peer-reviewed journals. E.g. an important paper published in Nature Biomedical engineering (2022). These papers have provided solid preclinical evidence of NAD+ and mitophagy in slowing down the pathologies of Alzhimer's disease (AD) in animal models. 2. Public scientific lectures and invited talks. Results of this project were presented in over 40 universities and instituttions (over the past 4 years), including talks in Oxford, Cambrdge, University of Copenhagen etc. This project has several positive impacts to the health services. 1. This study directly/indirectly supported the executation of a few NAD+-based clinical trials, one in the USA and another in Norway. As there is no drug to stop AD, the development of affordable and publicaly accessable drug candidates against AD are urgent. 2. The grant enabled the training of many students, inlcuding several postdocs (some were with their own funding) and several medical students. For many of them are successful in their career. E.g., one is now an associate Professor in China, one is an assistant professor in Spain, one is now a senior editor in the Nature Publication group. This grant also enabled the training of two talanted medical students from UiO and they also wrote a paper on NAD+. 3. This study increased the awareness of the general population (including AD patients and their families) to early prevention and fight against dementia, including AD. I was invited to present our data in episode 5 of Season 1 of the Award-winning NRK Documentary Demenskoret https://tv.nrk.no/serie/demenskoret. Our data were also presented in mainstream news papers in Norway, such as in VG (https://evandrofanglab.com/wp-content/uploads/2024/10/gxde2m4wwaajul_vg.jpg).

no

2023
In this HSØ grant 'Thurning up NAD+-induced mitophagy to treat Alzheimer's disease', we investigated the efficacy in using NAD+ precursors to treat Alzheimer's disease (AD). NAD+ reduced memory loss and pathlogies in AD mice. Mechanistically, this is significantly through NAD+-based improvement of circadian rhythm.This project is in progress as proposed. We have generated significant amout of data, with one big scientific paper published (https://pubmed.ncbi.nlm.nih.gov/34992270/). We are now working on the molecular mechanisms on how NAD+ regulates mitophagy as well as on how mitophagy regulates unknown pathways that are brain protective. The PhD student involved in this project is proposed to graduate in 2025. The success of this project will shed light on the development of novel drug candidate against AD and other related diseases.

no

2022
Our brain has its own 'garbage recycling system', and this 'garbage trunk' is named autophagy. To enable the running of the 'garbage truck', our brain needs to keep a highly functioning 'engine' (named mitochondria), via autophagic elimination of damaged mitochondria (mitophagy). We have identified causes of annulled mitophagy in AD.We have unveiled new causes of AD, including annulled PINK1-Parkin-dependent mitophagy. Accordingly, we have identified a few mitophagy inducers, from natural small molecules, as drug candidates for AD. The papers were published in peer-reviewed scientific journals, including in the leading journal Nature Biomedical Engineering (PMID: 34992270), Autophagy (PMID: 35130128), Mol Neurobiol.(PMID: 35739408). Popular science disseminations were implemented, including a FRONT PAGE news in the Saturday issue of VG (https://mynoad100.files.wordpress.com/2022/01/vg2022_alzheimers-e28093-vg.pdf) and an interivew in the popular NRK TV documentary Demenskoret (Episode 5 https://tv.nrk.no/serie/demenskoret), among other news and media coverings.

no

2021
Although the COVID-19 pandemic, significant progress has been made: 1. We are in the progress in characterizing mitophagy in postmortem AD brain tissues. 2. A novel mechanism that result in defective mitophagy in AD is unveiled.1. We are in the progress in characterizing mitophagy in postmortem AD brain tissues. By the application of brain tissues in the entorhinal cortex (EC), hippocampus (HIP), and prefrontal cortex (PFC) encompassing cognitive normal, Braak I/II, Braak III/IV, and Braak V/VI. Right we have finished data collection in the EC and HIP samples, and will be finishing collection in the PFC in 2022. 2. A novel mechanism that result in defective mitophagy in AD is unveiled. A novel protein was identified as the key of the mechanism, as this protein is reduced in AD, while genetic upregulation of this project improved mitophagy/autophagy and inhibited AD pathologies.

no

2020
The proportion of the elderly is increasing dramatically in Norway and worldwide; with 25% of the global population estimated to be 65+ years by 2100. Alzheimer’s disease (AD) is one of the most common diseases in the elderly, and affects 30-40 million people in the world.Molecular mechanisms on how NAD+ induces mitophagy, and on how the NAD+-mitophagy axis forestalls memory loss in both worm and mouse models of AD are under investigation. Methods on the generation of iPSC-derived neurons and glial cells are developed and will be used for further mechanistic studies and for screening of potential drug candidates. Human postmortem brain tissues (from a biobank in the UK) are available for the proposed experiments. A one-year researcher is working on this project with a 2-year postdoc is going to be recruited.

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Vitenskapelige artikler
Rice J, Lautrup S, Fang EF

NAD

Subcell Biochem 2024;107():63.

PMID: 39693020

Wang HL, Zhang J, Cao SQ, Lagartos-Donate MJ, Zhang SQ, Lautrup S, Hu Z, Lyssiotis CA, Houtkooper RH, Fang EF

A luminescent-based protocol for NAD

STAR Protoc 2024 Dec 20;5(4):103428. Epub 2024 nov 1

PMID: 39487980

Lyu YX, Fu Q, Wilczok D, Ying K, King A, Antebi A, Vojta A, Stolzing A, Moskalev A, Georgievskaya A, Maier AB, Olsen A, Groth A, Simon AK, Brunet A, Jamil A, Kulaga A, Bhatti A, Yaden B, Pedersen BK, Schumacher B, Djordjevic B, Kennedy B, Chen C, Huang CY, Correll CU, Murphy CT, Ewald CY, Chen D, Valenzano DR, Soldacki D, Erritzoe D, Meyer D, Sinclair DA, Chini EN, Teeling EC, Morgen E, Verdin E, Vernet E, Pinilla E, Fang EF, Bischof E, Mercken EM, Finger F, Kuipers F, Pun FW, Gyülveszi G, Civiletto G, Zmudze G, Blander G, Pincus HA, McClure J, Kirkland JL, Peyer J, Justice JN, Vijg J, Gruhn JR, McLaughlin J, Mannick J, Passos J, Baur JA, Betts-LaCroix J, Sedivy JM, Speakman JR, Shlain J, von Maltzahn J, Andreasson KI, Moody K, Palikaras K, Fortney K, Niedernhofer LJ, Rasmussen LJ, Veenhoff LM, Melton L, Ferrucci L, Quarta M, Koval M, Marinova M, Hamalainen M, Unfried M, Ringel MS, Filipovic M, Topors M, Mitin N, Roy N, Pintar N, Barzilai N, Binetti P, Singh P, Kohlhaas P, Robbins PD, Rubin P, Fedichev PO, Kamya P, Muñoz-Canoves P, de Cabo R, Faragher RGA, Konrad R, Ripa R, Mansukhani R, Büttner S, Wickström SA, Brunemeier S, Jakimov S, Luo S, Rosenzweig-Lipson S, Tsai SY, Dimmeler S, Rando TA, Peterson TR, Woods T, Wyss-Coray T, Finkel T, Strauss T, Gladyshev VN, Longo VD, Dwaraka VB, Gorbunova V, Acosta-Rodríguez VA, Sorrentino V, Sebastiano V, Li W, Suh Y, Zhavoronkov A, Scheibye-Knudsen M, Bakula D

Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.

Aging (Albany NY) 2024 Oct 16;16(20):12955. Epub 2024 okt 16

PMID: 39418098

Wang HL, Siow R, Schmauck-Medina T, Zhang J, Sandset PM, Filshie C, Lund Ø, Partridge L, Bergersen LH, Juel Rasmussen L, Palikaras K, Sotiropoulos I, Storm-Mathisen J, Rubinsztein DC, Spillantini MG, De Zeeuw CI, Watne LO, Vyhnalek M, Veverova K, Liang KX, Tavernarakis N, Bohr VA, Yokote K, Saarela J, Nilsen H, Gonos ES, Scheibye-Knudsen M, Chen G, Kato H, Selbæk G, Fladby T, Nilsson P, Simonsen A, Aarsland D, Lautrup S, Ottersen OP, Cox LS, Fang EF

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.

J Gerontol A Biol Sci Med Sci 2024 Apr 01;79(4).

PMID: 38289789

Lautrup S, Hou Y, Fang EF, Bohr VA

Roles of NAD

Cold Spring Harb Perspect Med 2024 Jan 02;14(1). Epub 2024 jan 2

PMID: 37848251

Fang EF, Tavernarakis N, Palikaras K

Editorial: Mitophagy in health and disease, volume II.

Front Cell Dev Biol 2023;11():1242664. Epub 2023 jun 29

PMID: 37457290

Xiong X, He H, Ye Q, Qian S, Zhou S, Feng F, Fang EF, Xie C

Alzheimer's disease diagnostic accuracy by fluid and neuroimaging ATN framework.

CNS Neurosci Ther 2023 Jul 12. Epub 2023 jul 12

PMID: 37438991

Dong Y, Zhuang XX, Wang YT, Tan J, Feng D, Li M, Zhong Q, Song Z, Shen HM, Fang EF, Lu JH

Chemical mitophagy modulators: Drug development strategies and novel regulatory mechanisms.

Pharmacol Res 2023 Aug;194():106835. Epub 2023 jun 20

PMID: 37348691

Knapskog AB, Aksnes M, Edwin TH, Ueland PM, Ulvik A, Fang EF, Eldholm RS, Halaas NB, Saltvedt I, Giil LM, Watne LO

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease.

Alzheimers Dement 2023 Dec;19(12):5573. Epub 2023 jun 2

PMID: 37264981

Cao SQ, Wang HL, Palikaras K, Tavernarakis N, Fang EF

Chemotaxis assay for evaluation of memory-like behavior in wild-type and Alzheimer's-disease-like C. elegans models.

STAR Protoc 2023 Apr 26;4(2):102250. Epub 2023 apr 26

PMID: 37104093

Xie C, Zhuang XX, Niu Z, Ai R, Lautrup S, Zheng S, Jiang Y, Han R, Gupta TS, Cao S, Lagartos-Donate MJ, Cai CZ, Xie LM, Caponio D, Wang WW, Schmauck-Medina T, Zhang J, Wang HL, Lou G, Xiao X, Zheng W, Palikaras K, Yang G, Caldwell KA, Caldwell GA, Shen HM, Nilsen H, Lu JH, Fang EF

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

Nat Biomed Eng 2022 Jan;6(1):76. Epub 2022 jan 6

PMID: 34992270

Ai R, Zhuang XX, Anisimov A, Lu JH, Fang EF

A synergized machine learning plus cross-species wet-lab validation approach identifies neuronal mitophagy inducers inhibiting Alzheimer disease.

Autophagy 2022 Apr;18(4):939. Epub 2022 feb 7

PMID: 35130128

Cao SQ, Aman Y, Fang EF, Tencomnao T

P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway.

Mol Neurobiol 2022 Sep;59(9):5612. Epub 2022 jun 23

PMID: 35739408

Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF

Autophagy in healthy aging and disease.

Nat Aging 2021 Aug;1(8):634-650. Epub 2021 aug 12

PMID: 34901876

Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF

Preclinical and clinical evidence of NAD

Mech Ageing Dev 2021 10;199():111567. Epub 2021 sep 10

PMID: 34517020

Gudmundsrud R, Skjånes TH, Gilmour BC, Caponio D, Lautrup S, Fang EF

Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome.

Cytogenet Genome Res 2021;161(6-7):297-304. Epub 2021 aug 25

PMID: 34433164

Zhang Y, Zhang Y, Aman Y, Ng CT, Chau WH, Zhang Z, Yue M, Bohm C, Jia Y, Li S, Yuan Q, Griffin J, Chiu K, Wong DSM, Wang B, Jin D, Rogaeva E, Fraser PE, Fang EF, St George-Hyslop P, Song YQ

Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway.

Brain 2021 10 22;144(9):2759-2770.

PMID: 34428276

Wang H, Lautrup S, Caponio D, Zhang J, Fang EF

DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer's Disease.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 jun 23

PMID: 34201700

Kobro-Flatmoen A, Lagartos-Donate MJ, Aman Y, Edison P, Witter MP, Fang EF

Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy.

Ageing Res Rev 2021 05;67():101307. Epub 2021 feb 20

PMID: 33621703

Zheng S, Rao J, Song Y, Zhang J, Xiao X, Fang EF, Yang Y, Niu Z

PharmKG: a dedicated knowledge graph benchmark for bomedical data mining.

Brief Bioinform 2020 Dec 21. Epub 2020 des 21

PMID: 33341877

Fang EF, Tao J

Targeting on the NAD

Aging Med (Milton) 2020 Sep;3(3):151-152. Epub 2020 sep 24

PMID: 33103034

Aman Y, Ryan B, Torsetnes SB, Knapskog AB, Watne LO, McEwan WA, Fang EF

Enhancing mitophagy as a therapeutic approach for neurodegenerative diseases.

Int Rev Neurobiol 2020;155():169-202. Epub 2020 aug 11

PMID: 32854854

Gilmour BC, Gudmundsrud R, Frank J, Hov A, Lautrup S, Aman Y, Røsjø H, Brenner C, Ziegler M, Tysnes OB, Tzoulis C, Omland T, Søraas A, Holmøy T, Bergersen LH, Storm-Mathisen J, Nilsen H, Fang EF

Targeting NAD

Mech Ageing Dev 2020 03;186():111208. Epub 2020 jan 15

PMID: 31953124

Deltagere
  • Shiqi Zhang Prosjektdeltaker
  • Sofie Lautrup Prosjektdeltaker
  • Hansang Cho Prosjektdeltaker
  • Zameel Cader Prosjektdeltaker
  • William McEwan Prosjektdeltaker
  • Nektarios Tavernarakis Prosjektdeltaker
  • Dag Årsland Prosjektdeltaker
  • Menno Witter Prosjektdeltaker
  • Tomás Schmauck-Medina Prosjektdeltaker
  • María José Lagartos-Donate Postdoktorstipendiat (annen finansiering)
  • Domenica Caponio Postdoktorstipendiat (finansiert av denne bevilgning)
  • Evandro Fei Fang Prosjektleder

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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