Author: Katerina Cechova

Success and Summary of the 2nd NO-AD International Meeting

Success and Summary of the 2nd NO-AD International Meeting

With the generous financial supports from the Nasjonalforeningen and from Iceland, Liechtenstein and Norway through the EEA Grants and the Technology Agency of the Czech Republic within the KAPPA Programme, the 2nd NO-AD International meeting was held on the 20th Oct 2021 in the Akershus University Hospital, Norway. This meeting had attracted close to 250 attendants, including 208 registered attendants via zoom and the remaining via physical attendance. The meeting was composed of 12 talks covering broad topics of the Alzheimer’s disease fields, including new molecular mechanisms of AD, the use of artificial intelligence in AD mechanistic studies and drug development, CRISPR- and gamma entrainment-based techniques on AD treatments, biomarker development for early stage of AD, and clinical treatments to AD patients. Our NO-AD international members Profs. Nancy Ip and Li-Huei Tsai were keynote speakers.

The meeting was also addressed by the principal investigators of the MIT-AD grant and their collaborators (Evandro F. Fang, Martin Vyhnalek, Liu Shi,  Jan Laczó, Katerina Cechova (Veverova) a Domenica Caponio).

Link of the meeting: here.

0:02:36 Nancy Ip (HKUST)  – ‘Biomarker development and genome-editing strategies for Alzheimer’s disease diagnosis and treatment’.
1:08:45 Alejo J Nevado-Holgado (Oxford) –  ‘Artificial Intelligence in Drug Target Discovery for Alzheimer’s Disease’.
1:38:49 Evandro Fang (Ahus, UiO) – ‘Turning up the NAD+-mitophagy axis to treat Alzheimer’s disease and the use of AI in related drug development’
2:04:25 Linda Hildegard Bergersen (UiO) – ‘Exercise and AD’
2:40:20 Kateřina Čechová (Charles University): – ‘Brain-derived neurotrophic factor (BDNF) in aging and Alzheimer disease’
2:58:27 Noel Buckley (Oxford): ‘Modelling Alzheimer’s in a dish – how far have we come?’.
3:51:17 Martin Vyhnálek (Charles University) ‘Subjective cognitive complaints – part of normal ageing or the beginning of Alzheimer’s disease?’
4:25:45 Tormod Fladby (Ahus, UiO) – ‘Challenges in early AD Diagnostics’
4:51:15 Jan Laczó (Charles University) – ‘Spatial navigation in Alzheimer disease’
5:22:43 Liu Shi (Oxford) – ‘Replication study of plasma biomarkers relating to Alzheimer’s pathology’
6:04:53 Domenica Caponio (UiO) – ‘Changes of mitophagy in the AD human brain’
6:19:28 Li-Huei Tsai (MIT) – ‘Non-invasive sensory stimulation to induce gamma entrainment and treat Alzheimer’s disease’

Presentations are available at this link.

NEW CHAPTER in Autophagy in Health and Disease (2nd Edition)!

NEW CHAPTER in Autophagy in Health and Disease (2nd Edition)!

Autophagy in Health and Disease, Second Edition provides a comprehensive overview of the process of autophagy and its impact on human physiology and pathophysiology. It expands on the scope of the first edition by covering a wider range of cell types, developmental processes, and organ systems.

Our chapter on Autophagic processes in early- and late-onset Alzheimer’s disease is focusing on the role of autophagy and mitophagy in the pathophysiology of Alzheimer’s disease.

Cover for Autophagy in Health and Disease


Autophagy plays a fundamental role in maintaining intracellular homeostasis and cell survival by degrading damaged and unnecessary subcellular components via the lysosome. Impaired autophagy is evident in otherwise “normal” elderly individuals and patients with neurodegenerative diseases, such as Alzheimer’s disease (AD). As the most common type of dementia, AD is an age-associated disease with memory loss as the primary clinical feature as well as extracellular Aβ plaques and intracellular Tau tangles as disease-defining pathological features. Recent studies in animal models of AD, AD patient-derived stem cells, and AD postmortem brain tissues suggest that compromised mitophagy/autophagy plays a causative role in AD progression. Supporting this hypothesis, pharmacological approaches to induce mitophagy/autophagy—e.g., the use of the small natural molecule oxidized nicotinamide adenine dinucleotide (NAD+)—slow AD progression in animal models. This chapter reviews the extant literature on autophagy in AD and covers recent progress on the molecular mechanisms of NAD+-dependent mitophagy/autophagy regulation and mechanisms underlying the anti-AD potential of NAD+. Further studies to define the NAD+-mitophagy/autophagy axis may shed light on novel therapeutics to treat AD and potentially provide insights into other neurodegenerative diseases.

Our chapter is available online here.

Welcome to attend the 2nd NO-AD meeting (20 Oct 2021) at the Akershus University Hospital, Norway

Welcome to attend the 2nd NO-AD meeting (20 Oct 2021) at the Akershus University Hospital, Norway

Date: 20th October 2021 (08:15-17:00, Central European Time/CET)
Venue: Seminar room S104.016, Akershus University Hospital, Sykehusveien 25, 1478, Norway
Registration: Virtual attendance (via zoom with link for registration below) or physical attendance (registration at the end of this website, limited seats)
Programme: Download here
Organisers: Evandro Fei Fang (University of Oslo), Martin Vyhnálek (Charles University), Noel Buckley (University of Oxford), Janet Jianying Zhang (University of Oslo)

Alzheimer’s disease (AD) is the most common dementia affecting 35-50 million individuals worldwide. Although it was discovered over 110 years ago, there is still no cure for AD despite decades of enormous effort. The big challenges right now are 1) the necessity for the unveiling of more of the molecular mechanisms leading to the development of AD; 2) creation of easily accessible and affordable approaches to identify individuals with early AD to facilitate earlier intervention and treatment; 3) strategies or treatments to delay, slow down or prevent AD are urgently needed; and 4) the necessity for accellerating the development of effective anti-AD drugs or therapies using modern techniques (e.g., CRISPR-Cas9 and artificial intelligence/AI). After the success of the 1st NO-AD meeting (website here and recorded videos here) on the 25th Nov 2020, we are pleased to open the 2nd NO-AD meeting on the 20th Oct. 2021 to be jointly organized by The University of Olso (UiO, Norway) and Akershus University Hospital (Ahus, Norway), The University of Oxford (Oxford, UK), and Charles University (CU, Czech Republic).

This one-day hybrid meeting (physical attendance + Zoom) will provide updates on all these important topics with talks by leading experts in their fields. We are very pleased to have two keynote speakers, Prof. Nancy Ip (HKUST, Hong Kong) and Prof. Li-Huei Tsai (MIT, USA) to open and close this one-day talk, respectively. Other speakers will be Associate Professor Alejo J. Nevado-Holgado (Oxford, UK), Associate Professor Evandro F. Fang (UiO/Ahus, Norway), Prof. Noel Buckley (Oxford, UK), Professor Linda Hildegard Bergersen (UiO/Ahus, Norway), Dr. Katerina Cechova (Charles University, Czech Republic), Associate Professor Martin Vyhnálek (Charles University, Czech Republic), Professor Tormod Fladby (UiO/Ahus, Norway), Prof. Jan Laczó (Charles University, Czech Republic), Dr. Liu Shi (Oxford, UK), and Dr. Domenica Caponio (UiO/Ahus, Norway).

Zoom registration (not for physical attendance):

Physical attendance: If you want to attend physically, please register at the end of this page. Note, due to the COVID-19 control, we only can fit 36 seats in the meeting room. First register first serve. We will send you an email 1-2 weeks before the meeting whether there is a seat for you or not.

Registration (for physical attendance)

A new hypothesis on AD has been published

A new hypothesis on AD has been published

Assoc. Prof. Evandro F. Fang and his team published a new hypothesis on AD in Ageing Research Reviews 2021. For full-text click here.

Proposed mechanism of the occurrence of the earliest AD pathology in entorhinal cortex (EC) L-II: linkages of impaired mitophagy which leads to impaired mitochondrial homeostasis, in Abeta and Tau pathologies are presented. (A) Immunofluorescently labeled reelin-positive neuronal population in L-II of rat EC. (B-C) Schematic representation of the signal transduction cascade generated by reelin under normal physiological conditions (B) vs AD (C). (B) Under normal conditions, including in young individuals, reelin is highly expressed. Reelin binds to lipoprotein receptors, such as ApoER2 and VLDLR, inducing activation of Disabled 1 (Dab1), an adapter protein. Activated Dab1 induces activation of Src family kinases (SFKs) that potentiate tyrosine phosphorylation of Dab1, which in turn activates Phosphoinositide 3-kinase (PI3K) and subsequently protein kinase B (PKB). PKB activation inhibits the activity of GSK3β, thereby reducing p-Tau and promoting microtubule stability. PKB also activates mTOR-dependent processes which promote the outgrowth of dendrites and balances mitochondrial biogenesis and autophagy. Changes of mTOR activity affect the activities of ULK1, AMPK, sirtuins (SIRTs), FOXOs, and NAD+. In addition, ApoER2-reelin complex is coupled to NMDAR signaling through PSD95. Reelin-activated SFK phosphorylates NMDAR and potentiates NMDAR-Ca2+ influx. Influx of Ca2+ activates the transcriptional regulator, CREB, through which expression of genes important for synaptic plasticity and neurite growth are potentiated. CREB-regulated genes encode proteins important for learning and memory. Astrocyte- and neuron-derived ApoEs bind to ApoER2 and are constitutively internalized. Upon reelin signaling, ApoER2 also undergoes endocytosis. In the cases of ApoE2 and ApoE3, ApoER2 is efficiently recycled to the cell membrane; this is impaired in the case of ApoE4. In healthy young individuals, mitophagy effectively clears damaged mitochondria, ensuring a healthy mitochondrial pool in the high-energy demanding axon terminals; this enables normal neuronal function and neuronal plasticity. Mitophagy also eliminates intracellular iAβ1-42 and pathological Tau proteins. (C) Ageing is the primary driver of AD with multiple molecular mechanisms involved, including age-dependent reduction of reelin and impaired mitophagy (also autophagy). In prodromal AD, reduced reelin in the EC L-II neurons impairs the control of the ApoER2/VLDLR-Dab-1-PI3K-PKB-GSK3β axis, leading to pTau. Furthermore, iAβ1-42 is increased in the EC L-II neurons, possibly due to increased production (via ApoE4-dependent trapping, detailed below), and reduced clearance by impaired mitophagy/autophagy. iAβ1-42 may bind reelin and thereby reduce levels of signaling competent reelin, in turn impairing PKB mediated inhibition of GSK3β and thus increasing p-Tau. ApoE4 may accentuate this as it tends to get trapped in endosomes along with its lipoprotein receptors, likely mainly ApoER2. This in turn further reduces reelin-signaling, boosting the cascade leading to p-Tau. In concert, ApoE4, trapped in endosomes, increases transcription of APP and thus production of iAβ1-42, and thereby completes a vicious cycle, whose end product for the affected neurons are NFTs. Furthermore, reduced PKB-activity also inhibits mTOR activity, impacting on mitochondrial homoeostasis and autophagy. Moreover, ApoE4 sequesters ApoER2 in intracellular compartments and reduces the NMDAR phosphorylation in response to reelin in the postsynaptic neuron, leading to impaired neural plasticity. In line with the age onset of AD, age-dependent mitophagy impairment causes accumulation of damaged mitochondria, which further exacerbates AD pathology, including shortage of energy supply, inflammation, oligomerization of iAβ1-42 and pathological Tau proteins, finally leading to impaired LTP and neuronal plasticity, and neuronal loss. Individuals carrying ApoE4 may have exacerbated mitophagy impairment since ApoE4 inhibits TFEB-dependent regulation of autophagy- and lysosome-related genes. Dashed lines and faint phosphorylation symbols indicate blunted signaling capacity. Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; AMPK, 5′ AMP-activated protein kinase; ApoE, apolipoprotein E; ApoER2, ApoE receptor 2; Ca2+, calcium ion; CREB, cAMP response element-binding protein; Dab1, disabled 1; EC, entorhinal cortex; FOXOs, Forkhead box O (FOXO) transcription factors; GSK3β, glycogen synthase kinase 3β; LTP, Long-term potentiation; NMDAR, N-methyl-D-aspartate receptor; PKB, protein kinase B; SIRTs, the NAD+-dependent deacetylates sirtuins; SFKs, SRC family tyrosine kinases; ULK1, unc-51 like autophagy activating kinase 1; VLDLR, very-low-density lipoprotein receptor; low-density lipoprotein receptor-related protein 1 (LRP1). Dashed arrows indicate impaired induction/activation.

Figure: Asgeir Kobro-Flatmoen…Evandro F. Fang, Ageing Research Reviews 2021