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Combined Metabolic Activators Improves Cognitive Functions in Alzheimer's Disease

56 Pages Posted: 15 Sep 2021

See all articles by Burak Yulug

Burak Yulug

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience

Ozlem Altay

Royal Institute of Technology (KTH) - Science for Life Laboratory (SciLife Lab)

Xiangyu Li

Royal Institute of Technology (KTH) - Science for Life Laboratory

Lutfu Hanoglu

Istanbul Medipol University - Department of Neurology

Seyda Cankaya

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience

Simon Lam

King’s College London - Centre for Host-Microbiome Interactions

Hong Yang

Royal Institute of Technology (KTH) - Science for Life Laboratory

Ebru Coskun

Istanbul Medipol University - Department of Neurology

Ezgi Idil

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience

Rahim Nogaylar

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience

Cemil Bayram

Atatürk University - Department of Medical Pharmacology

Ismail Bolat

Atatürk University - Department of Pathology

sena oner

Erzurum Technical University - Department of Molecular Biology and Genetics

Ozlem Ozdemir Tozlu

Erzurum Technical University - Department of Molecular Biology and Genetics

Mehmet Enes Arslan

Erzurum Technical University - Department of Molecular Biology and Genetics

Ahmet Hacimuftuoglu

Atatürk University - Department of Medical Pharmacology

Serkan Yildirim

National Research Institute of Electronics and Cryptology (UEKAE)

Muhammad Arif

Royal Institute of Technology (KTH) - Science for Life Laboratory

Saeed Shoaie

King's College London - Centre for Host-Microbiome Interactions

Cheng Zhang

Royal Institute of Technology (KTH) - Science for Life Laboratory

Jens Nielsen

Chalmers University of Technology - Department of Biology and Biological Engineering

Hasan Turkez

Atatürk University - Department of Medical Biology

Jan Boren

University of Gothenburg - Department of Molecular and Clinical Medicine

Mathias Uhlen

Royal Institute of Technology (KTH) - Science for Life Laboratory

Adil Mardinoglu

Royal Institute of Technology (KTH) - Science for Life Laboratory

More...

Abstract

Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMA), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMA includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMA improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMA improves cognitive functions in AD patients. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group. We also observed a significant decrease in the placebo group on Day 84 vs Day 0 (Log2FC= -0.19, (14% improvement), p-value=0.001) possibly due to the recommendations of exercise and Mediterranean diet to all AD patients and/or a placebo effect apparent in the early stages of AD clinical trials. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases.

Funding: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Metabolon Inc. (Durham, USA) for generation of metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Skłodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union’s Horizon 2020 research and innovation programme.

Declaration of Interest: AM, JB and MU are the founder and shareholders of ScandiBio Therapeutics. The other authors declare no competing interests.

Ethical Approval: All experiments for the treatment of the animals were approved by the Ethics Committee of Atatürk University, and were conducted following the National Institutes of Health Guide for Care and Use of Laboratory Animals.

Keywords: Alzheimer's disease: Combined Metabolic Activators (CMA), Multi-omics analysis, Systems Biology, Systems Medicine

Suggested Citation

Yulug, Burak and Altay, Ozlem and Li, Xiangyu and Hanoglu, Lutfu and Cankaya, Seyda and Lam, Simon and Yang, Hong and Coskun, Ebru and Idil, Ezgi and Nogaylar, Rahim and Bayram, Cemil and Bolat, Ismail and oner, sena and Tozlu, Ozlem Ozdemir and Arslan, Mehmet Enes and Hacimuftuoglu, Ahmet and Yildirim, Serkan and Arif, Muhammad and Shoaie, Saeed and Zhang, Cheng and Nielsen, Jens and Turkez, Hasan and Boren, Jan and Uhlen, Mathias and Mardinoglu, Adil, Combined Metabolic Activators Improves Cognitive Functions in Alzheimer's Disease. Available at SSRN: https://ssrn.com/abstract=3924201 or http://dx.doi.org/10.2139/ssrn.3924201

Burak Yulug

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience ( email )

Antalya
Turkey

Ozlem Altay

Royal Institute of Technology (KTH) - Science for Life Laboratory (SciLife Lab) ( email )

Lindstedtsvägen 30-100 44
Stockholm, SE-100 44
Sweden

Xiangyu Li

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Lutfu Hanoglu

Istanbul Medipol University - Department of Neurology ( email )

Istanbul
Turkey

Seyda Cankaya

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience ( email )

Antalya
Turkey

Simon Lam

King’s College London - Centre for Host-Microbiome Interactions

London
United Kingdom

Hong Yang

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Ebru Coskun

Istanbul Medipol University - Department of Neurology ( email )

Istanbul
Turkey

Ezgi Idil

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience ( email )

Antalya
Turkey

Rahim Nogaylar

Alanya Alaaddin Keykubat University - Department of Neurology and Neuroscience ( email )

Antalya
Turkey

Cemil Bayram

Atatürk University - Department of Medical Pharmacology ( email )

Erzurum
Turkey

Ismail Bolat

Atatürk University - Department of Pathology ( email )

Erzurum
Turkey

Sena Oner

Erzurum Technical University - Department of Molecular Biology and Genetics ( email )

Erzurum
Turkey

Ozlem Ozdemir Tozlu

Erzurum Technical University - Department of Molecular Biology and Genetics ( email )

Erzurum
Turkey

Mehmet Enes Arslan

Erzurum Technical University - Department of Molecular Biology and Genetics ( email )

Erzurum
Turkey

Ahmet Hacimuftuoglu

Atatürk University - Department of Medical Pharmacology ( email )

Erzurum
Turkey

Serkan Yildirim

National Research Institute of Electronics and Cryptology (UEKAE) ( email )

Turkey

Muhammad Arif

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Saeed Shoaie

King's College London - Centre for Host-Microbiome Interactions ( email )

United Kingdom

Cheng Zhang

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Jens Nielsen

Chalmers University of Technology - Department of Biology and Biological Engineering ( email )

SE-412 96 Goteborg
Sweden

Hasan Turkez

Atatürk University - Department of Medical Biology ( email )

Erzurum, 25240
Turkey

Jan Boren

University of Gothenburg - Department of Molecular and Clinical Medicine ( email )

PO Box 400
Göteborg, SE405 30
Sweden

Mathias Uhlen

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Adil Mardinoglu (Contact Author)

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

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