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From mitophagy to neurocognitive impairment

From mitophagy to neurocognitive impairment

Discover the cutting-edge world of mitochondrial research at the upcoming conference, “From Mitophagy to Neurocognitive Impairment,” hosted by the Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital with the University in Oslo. Join us in exploring more about mitophagy and cognitive health.

The conference program brings up-to-date findings in the neurodegenerative cascade of Alzheimer’s disease. We will start with the knowledge about mitophagy (the mechanism of recycling damaged mitochondria), whose disruption may be at the very beginning of the disease, and the possibilities of its therapeutic influence. We will also present brain organoids modeling the pathophysiology and blood-based biomarkers reflecting Alzheimer’s pathology in preclinical and clinical studies. We will not omit the most common clinical manifestations in patients, including methods of experimental neuropsychology, and conclude with a look into the future treatment of this insidious disease.

Event Details:

  • Date: 11 April 2024
  • Time: 8.30—17.00
  • Venue: Vlastenecký sál, Karolinum (Ovocný trh 3, Praha 1)

You can look forward to a day packed with insightful talks by leading experts, engaging discussions, and valuable networking opportunities, including:

Nektarios Tavernarakis ► Mitophagy in basic research

Evandro F. Fang ► Brain health & longevity

Dáša Bohačiaková ► Brain organoids in AD

Giovanni Bellomo ► Blood-based biomarkers in AD

Jakub Hort ► Perspectives in AD treatment

Kateřina Sheardová ► Well-being & brain maintenance

Program details are available here

Hybrid Format: This conference offers a unique hybrid format, providing you the flexibility to choose between attending in person or participating online.

Free registration required: Ensure your spot for both online and in-person participation by registering here. Do not hesitate, as space is limited.

We look forward to sharing this enlightening experience with you.

Summary of MiT AD project activities in 2023

Summary of MiT AD project activities in 2023

At Charles University, Prague, 180 participants were screened, and 40 were accepted to participate in the study and were examined according to the complex clinical protocol (in this third year we recruited mainly patients with non-AD dementia linked to the planned FTLD paper). In the third year, we analyzed 360 biofluid samples from individuals recruited in the MitAD study. We have continued to measure five mitophagy biomarkers – PINK1 (MyBioSource, MBS7607221), ULK1 (FineTest, EH4191), BNIP3L (FineTest, EH6731), REST (MyBioSource, MBS9354282) and TFEB (MyBioSource, MBS7612687) – these markers together should reflect all five steps of mitophagy process. Additionally, we analyzed standard AD biomarkers – Aβ 1-42, Aβ 1-40, total tau, p-tau 181 (EuroImunn), and a marker of neurodegeneration – neurofilament light chain (UmanDiagnostics) – in another 120 individuals to define the study cohort.

At the University of Oslo, Norway, we have finalized the wet laboratory study investigating roles of ULK1 in neuroprotection. We especially focused on the molecular mechanisms on how ULK1 inhibits AD pathologies: we show that ULK1 increases microglial phagocytosis to eliminate Abeta plaques in the ULK1;5xFAD mice; congruently, ULK1 reduces pTau activities by eliminating kinases that phosphorylate Tau. We have prepared a paper entitled ‘Age-dependent autophagy impairment risks Alzheimer’s disease due to ULK1 reduction’. The entire manuscript was uploaded to the application.  

Publications

Oslo team also participated in two original papers 1) In the paper on kynurenic acid in AD, we found that the NAD+ de novo synthetic pathway intermediate kynurenic acid inhibits AD progression (Knapskog AB et al., Alzheimer’s Dement 2023, IF = 14.7) 2) another NAD+ de novo synthetic pathway intermediate quinolinic acid risk death of patients with delirium (Watne LO, et al., J Clin Invest 2023, IF = 15.9).

We published two review papers focused on 1) chemical mitophagy modulators and drug development (Chemical mitophagy modulators: Drug development strategies and novel regulatory mechanisms; Pharmacological Research, IF=9.3 2) the relation between mitophagy and neuroinflammation (Mitophagy and Neuroinflammation: A Compelling Interplay; Current Neuropharmacology, IF = 5.3) and an editorial (Editorial: Mitophagy in health and disease, volume II; Frontiers in Cell and Developmental Biology, IF = 5.5). All papers were published in impacted journals indexed in Web of Science, and the dedication to the Kappa project was acknowledged.

In September, we submitted a research article Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer’s disease in the Autophagy journal (IF=13.3). Currently, the paper is in the second round of revision, with very favorable feedback from the reviewers. In this study, we quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1/BNIP3L and TFEB, respectively) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n=100), dementia due to AD (AD-dementia, n=100), and cognitively unimpaired individuals (CU, n=46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Our study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology. 

The research article, Serum PAI-1/BDNF Ratio is increased in Alzheimer’s disease and correlates with disease severity, was published in October in ACS Omega Journal (IF= 4.13). In this study, we examined levels of proteins included in neuroprotective molecular pathways (BDNF, PAI-1, tPA) in the serum of patients with dementia due to AD, MCI due to AD, and cognitively unimpaired individuals. We found that BDNF serum levels are lower (13.7% less), and PAI-1 levels are higher in Alzheimer patients with dementia than in Alzheimer patients with amnestic mild cognitive impairment patients (23% more) or controls (36% more). Furthermore, the PAI-1/BDNF ratio was significantly increased in Alzheimer patients as compared to amnestic mild cognitive impairment (36.4% more) and controls (40% more). Lastly, the PAI-1/BDNF ratio negatively correlated with cognition. The study analysed the samples collected in MitAD project and used also the clinical data from the project.

The second research article, Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration, was accepted by the Journal of Cellular and Molecular Medicine (IF= 5.3) in October. In this research article, we investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in the serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty-five FTLD patients (21 in the mild cognitive impairment stage (MCI) and 14 in the dementia stage) and 10 cognitively healthy controls were recruited. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls and also negatively correlated with the cognitive measures. The study analysed the samples collected in MitAD project as well and used also the clinical data from the project.

Both articles were dedicated to the MitAD project and uploaded to the online open repository Zenodo.

(Invited) Review article Diagnostika Alzheimerovy nemoci a ostatních neurodegenerativních onemocnění pomocí biomarkerů z mozkomíšního moku a krve for a Czech journal Neurologie pro praxiwas also accepted in October 2023. In this review paper, we summarized the current overview of biofluid biomarkers in AD. We described the current state of knowledge in diagnosing AD: the golden standard of CSF biomarkers, the biomarkers of non-specific processes that accompany neurodegenerative diseases, and proposed the future use of experimental biomarkers such as mitophagy markers.

Conferences

In July, the MitAD team attended the Alzheimer’s Association International Conference (AAIC) in Amsterdam, Netherlands. Dr. Veverova and Assoc. Prof. Vyhnálek presented a poster Mitophagy biomarkers are changed in Alzheimer’s disease continuum, where she summarized the findings of mitophagy markers in the AD continuum. The results were later on used for the paper Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer’s disease that was submitted recently. MSc. Katonova presented a poster with the title Levels of mitophagy biomarkers differ between individuals with Alzheimer’s disease and frontotemporal lobar degeneration. In this research, we identified different patterns in levels of mitophagy biomarkers in individuals with FTLD compared to AD and controls. Currently, we are preparing the manuscript elaborating on these preliminary findings.

On 18-19 September 2023, the MitAD team co-organized the 1st Norway-UK joint meeting on aging and dementia in Oslo, hosted by Evandro F. Fang (the University of Oslo and Akershus University Hospital, Norway), Lynne Cox (University of Oxford, UK) and Richard Siow (King’s College London, UK). The meeting was opened by educational and political leaders of the two nations, including Prof. Per Morten Sandset (Vice-Rector for Research and Innovation of the University of Oslo), Clare Filshie (Deputy Head of Mission from the British Embassy in Oslo), and Øystein Lund (Counsellor for Research and Education from the Royal Norwegian Embassy in London). Assoc. Prof. Vyhnalek and Dr. Veverova presented their findings from the MitAD project entitled Alterations of human CSF and serum-based mitophagy biomarkers patients from Czech Brain Aging Study (CBAS). The meeting attracted over 40 experts and scholars from 13 countries, including China, Denmark, Greece, Japan, Norway, the United Kingdom, the United States, and others. They gathered to share the latest research findings on various aspects of global ageing and to engage in discussions and workshops on topics including mechanisms of human ageing (such as genetic risk factors, DNA damage and repair, mitophagy and autophagy, etc), connections between ageing processes and disease, and promoting a healthy ageing environment. including. Importantly, discussions included potential interventions to reduce biological ageing and translation of research findings into clinical application. The meeting summary with a title:Meeting summary of The NYO3 5th NO-Age/AD meeting and the 1st Norway-UK joint meeting on ageing and dementia: recent progress on the mechanisms and interventional strategies will be published in the Journal of Gerontological series A (IF = 5.1).

Additionally, several lectures were presented and dedicated to the MitAD project last year.

Prof. Evandro F. Fang visited the Second Faculty of Medicine, Charles University in Prague in June 2023. During his visit, he delivered his lecture on novel mechanisms activating mitophagy from the brain at the Department of Neurology. It was an excellent opportunity for clinicians to learn new approaches to preventing aging and AD. On this occasion, he gave an interview to a hospital magazine, Motol IN, intended for patients and the general public.

In September, Dr. Veverova presented results from the MitAD project during the invited lecture The role of mitophagy in AD pathophysiology at ADDIT-CE: AD-workshop 2 in Brno, Czech Republic. This workshop was attended by 40 scientists.

In another invited lecture, Dr.Veverova, presented the concept of blood-based biomarkers in AD research Krevní biomarkery Alzheimerovy nemoci – budoucnost na dohled? at the 6th Ostrava Liquor Symposium. This symposium is organized for biochemists and clinicians to share the latest developments in liquor diagnosis of various neurological diseases.

An undergraduate student of the MitAD team, Mrs. Alzbeta Katonova, defended her master thesis entitled Mitophagy biomarkers in the continuum of Alzheimer’s disease, supervised by Dr. Veverova and Assoc. Prof. Vyhnalek, with an excellent evaluation. This thesis was chosen out of 244 master theses in the top 10 for the Werner von Siemens Award.

Workshop on Alzheimer’s dementia in Brno

Workshop on Alzheimer’s dementia in Brno

In September, Dr. Veverova and Assoc. Prof. Vyhnalek attended the ADDIT-CE workshop in Brno. The workshop was primarily focused on basic research with topics such as stem-cell based models in AD research, Abeta self-assembly, mechanical stress on axons and more. Dr. Veverova presented results from the MitAD project during the invited lecture The role of mitophagy in AD pathophysiology.

The 5th NYO3 NO-Age/AD meeting and the 1st Norway-UK joint meeting on ageing and dementia

The 5th NYO3 NO-Age/AD meeting and the 1st Norway-UK joint meeting on ageing and dementia

Assoc. Prof. Evandro F. Fang with Dr. Katerina Veverova and Assoc. Prof. Martin Vyhnalek

On 18-19 September 2023, the MitAD team co-organized the 1st Norway-UK joint meeting on aging and dementia in Oslo, hosted by Evandro F. Fang (the University of Oslo and Akershus University Hospital, Norway), Lynne Cox (University of Oxford, UK) and Richard Siow (King’s College London, UK). The meeting was opened by educational and political leaders of the two nations, including Prof. Per Morten Sandset (Vice-Rector for Research and Innovation of the University of Oslo), Clare Filshie (Deputy Head of Mission from the British Embassy in Oslo), and Øystein Lund (Counsellor for Research and Education from the Royal Norwegian Embassy in London). Assoc. Prof. Vyhnalek and Dr. Veverova presented their findings from the MitAD project entitled Alterations of human CSF and serum-based mitophagy biomarkers patients from Czech Brain Aging Study (CBAS). The meeting attracted over 40 experts and scholars from 13 countries, including China, Denmark, Greece, Japan, Norway, the United Kingdom, the United States, and others. They gathered to share the latest research findings on various aspects of global ageing and to engage in discussions and workshops on topics including mechanisms of human ageing (such as genetic risk factors, DNA damage and repair, mitophagy and autophagy, etc), connections between ageing processes and disease, and promoting a healthy ageing environment. including. Importantly, discussions included potential interventions to reduce biological ageing and translation of research findings into clinical application.

Interview with Evandro F. Fang in Motol IN

Interview with Evandro F. Fang in Motol IN

Assoc. Prof. Evandro F. Fang visited the Second Faculty of Medicine, Charles University in Prague in June. During his visit, he delivered his famous lecture on novel mechanisms activating ‘garbage cleaning’ (mitophagy) from the brain at the Department of Neurology. It was an excellent opportunity for clinicians to learn new approaches to preventing aging and Alzheimer’s disease. On this occasion, he gave an interview to a hospital magazine, Motol IN, intended for patients and the general public.

You can find the issue with the article “Removing brain ‘garbage’ as a pathway to healthy brain” online here (Motol IN č.7-8/2023).

Here we provide the original version in English:

  1. You recently received an award for your excellent dementia research (National Association for Public Health’s Dementia Research Prize for 2023). What does such an award mean to you and your team?

EFF: It was such a big honour as a laureate of the National Association for Public Health’s Dementia Research Prize for 2023 presented by H.M. King Harald V of Norway. This is among the most prestigious awards in the science fields in the Scandinavian countries, and is to give recognition to researchers or clinicians who have contributed significantly to the understanding or treatment of dementia. Such a big award to a young research, it really encourages me to work harder on the way to find a cure for Alzheimer’s disease, the most common dementia worldwide.

  • What is the best way to improve human mitochondrial function? Can we change anything in our lifestyle?

EFF: Mitochondria are the powerhouses of our body and mitochondria are dynamic (fusion and fission) and fragile. It has been reported in both laboratory and clinical studies that interventions like exercise and healthy diet can improve mitochondrial numbers and quality. Exercise and healthy diets are public accessible approaches to work with.

  • You have been working as a researcher in the US and in Norway. How do the conditions for scientists in the two countries differ?

EFF: I have been working in Hong Kong (4 years), Baltimore in the USA (6 years), and Oslo (Norway, almost 6 years). I have had great and positive experiences in studying and living in these charming cities. Speaking of science they are different: the working speed is Hong Kong is very fast and professional; in the USA, the research competitive is very high and among the highest quality; in Norway, the funding is very decent and the research environment is open and thus one can have a great balance of life and scientific career.

  • What would you advise young researchers to succeed in their careers?

EFF: To set up a goal of your career, and based on this goal to develop your training plans and to rich your CV. Definitely, in such a world with international competition in most scientific jobs, we need to work hard in a happy way. A key to make us happy is to choose the career that one really love.

  • In your opinion, what is the most pressing research question that needs to be addressed in the field of mitophagy and Alzheimer’s disease?

EFF: Our 2019 paper on Nature Neuroscience is considered a milestone on targeting defective mitophagy as a druggable target for Alzheimer (with more than 800 citations since 2019). Since then great efforts by many other labs and us have done on the mechanistic studies of defective mitophagy in Alzheimer as well as on the development of novel drug candidates for Alzheimer. Some novel mitophagy-inducing molecules show great anti-Alzheimer activity in laboratory models and human iPSC-derived cellular systems; furthermore, these molecules are bioavailability, with favoured pharmacokinetics, and some can pass the blood-brain barrier. Thus, the most pressing question is to test them in clinical trials for Alzheimer. 

  • Can you tell us your assumption when will be possible to treat Alzheimer’s disease causally?

EFF: Alzheimer’s is likely a group of diseases which make it challenging to find a drug to cure all individuals with Alzheimer’s. The exciting news on the 25-35% efficacy in reducing memory loss of newly developed anti-Abeta antibodies bring us hope. Targeting on offsetting defective mitophagy may show a more profound benefit as it could reduce many risks/causes of Alzheimer’s (Nature Review Drug Discovery Turning up mitophagy in Alzheimer disease – PubMed (nih.gov)

First Norway-UK meeting on ageing and dementia

First Norway-UK meeting on ageing and dementia

Welcome to join us the 1st Norway-UK meeting on ageing and dementia on 18-19 Sep. 2023!

We are pleased to invite you to this exciting meeting, where scientists from the most prestigious universities will share their research on aging and dementia. Assoc. Prof. Evandro F. Fang is an organizer of this event, where Assoc. Prof. Martin Vyhnalek and Dr. Katerina Veverova will present the results of the MitAD project on mitophagy biomarkers in the AD continuum.

Registration is not required and attendance at all events will be free of charge.
On-line attendance https://uio.zoom.us/webinar/register/WN_XBxzUlSqTEOGwnYawHH7BQ

More info: https://noage100.com/

MitAD team at AAIC 2023

MitAD team at AAIC 2023

Our team had the great opportunity to present our preliminary results of the MitAD project at AAIC 2023 in Amsterdam. We enjoyed talking to researchers from all over the world and sharing our exciting discoveries on mitophagy across the Alzheimer’s disease continuum. Just like we enjoyed the informal time with the whole Czech Brain Aging Study (CBAS) team.

Assoc. Prof. Evandro F. Fang in Prague

Assoc. Prof. Evandro F. Fang in Prague

Assoc. Prof. Evandro F. Fang gave an excellent lecture on novel mechanisms activating ‘garbage cleaning’ (mitophagy) from the brain at the Department of Neurology, Second Faculty of Medicine in Prague. It was a great opportunity for clinicians to learn new approaches to preventing aging and AD. Also, we had some time to explore Czech cuisine and nature.