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Principal Investigator  
Principal Investigator's Name: Yahyah Aman
Institution: University of Oslo
Department: Department of Clinical Molecular Biology
Proposed Analysis: Alzheimer’s disease (AD) affects 44.5 million people worldwide and causes formidable economic challenges. Over the last 15 years, 244 AD drug candidates, predominantly targeting tau and Aβ, were tested in clinical trials. However, only one, an agent that mitigates symptoms rather than disease progression, received approval from the US FDA and European Medicines Agency. This suggests that successful treatments may be found by investigating other molecular mechanisms in AD aetiology and progression. Mitochondria are essential for neuronal development and function due to their role in ATP production and cell signalling. Mitochondrial quality is tightly regulated by mitophagy, in which damaged mitochondria are degraded and recycled. Mitophagy in neurons is necessary to prevent neuronal cell death and pathogenic brain aging. Indeed, our preliminary data show severe defective mitophagy in post-mortem brain tissues from AD patients and AD induced pluripotent stem cell (iPSC)-derived neurons, and restoration of mitophagy inhibits memory loss in an AD mouse model. This proposed project represents a potential paradigm shift in AD research, placing mitophagy and mitochondrial health front and centre in AD aetiology. Further understanding the mechanisms of mitophagy and its roles in neurodegeneration may revolutionize our understanding of AD and propel clinical drug discovery in new and more fruitful directions. AD-associated brain abnormalities occur decades prior to any clinical presentation of symptoms. Thus, early diagnosis of the disease is important and is considered to be the most promising window of opportunity for disease-modifying drugs. AD-specific biomarkers have been recognized as a powerful tool for early diagnosis and treatment of AD in clinic that can reflect pathological manifestations with a greater degree of accuracy. Examples of which include: positron emission tomography (PET) neuroimaging evaluating glucose metabolism thus brain neuronal activity; magnetic resonance imaging (MRI) revealing cortical atrophy; and cerebrospinal fluid (CSF) analysis that depicts increase in total tau concentration, indicative of neurodegeneration, p-tau, reflecting presence of NFT, and reduced pro-aggregating Aβ1-42 that represents reduction of its brain clearance, thus greater amyloid pathology. In addition, PET tracers that bind Aβ display increased amyloid burden in AD individuals. At present, it is a combination of neuroimaging and CSF analysis that has led to in vivo diagnosis and reflection of disease progression. However, drugs targeting Aβ and tau have largely been unsuccessful in clinical trials, highlighting the necessity to pursue in identification of other biomarkers and mechanism that can be therapeutically targeted. To date, there is limited evidence on mitochondrial dysfunction and mitophagy biomarkers in AD, with previous studies providing contradicting observations of CSF concentration of mitochondrial DNA in AD. Thus here we propose to identify novel mitophagy biomarkers in AD. For this purpose, firstly, we aim to identify and evaluate changes in mitophagy-related genes (i.e. (i.e. BNIP3L/NIX, Parkin, PINK1, and ULK1) (genetic dataset) and protein expression (biomarkers in CSF and plasma) in patients with AD, mild cognitive impairment (MCI), and healthy control. Subsequently, we propose to elucidate the association of mitophagy-related gene/protein expression to predict 1) structural changes (MRI dataset): 2) AD pathology and neuroinflammation (biomarkers and PET imaging dataset); and 3) degree of cognitive impairment. Altogether, we will therefore be identifying markers of mitophagy underlying mitochondrial dysfunction in CSF and plasma of clinical AD patients and its association AD aetiology and progression.
Additional Investigators