Title : Elucidating the consequences of mitochondrial dysfunction on alzheimer’s pathology
Abstract:
Alzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive impairment, characterized by progressive cognitive decline, memory loss, and neuronal death in the cerebral cortex, hippocampus, and other brain regions. Hallmarks of its pathology are amyloid beta (Aβ) plaques, neurofibrillary tangles of hyperphosphorylated tau, dysfunctional mitochondria and neuroinflammation. Mechanisms and relationship to the progression of AD are not well understood. For these reasons, our research focused on analyzing and extrapolating the effects of mitochondrial dysfunction, tau pathology, oxidative stress secondary to ROS production, ADAM10 (Alpha secretase) expression, and BACE1 (β-secretase) expression in MCI (Mild Cognitive Impairment) and AD groups. ADAM10 and BACE1 are enzymes involved in cleaving amyloid precursor protein (APP). ADAM10 forms non-amyloidogenic APPα and BACE1forms amyloidogenic APPβ, which undergoes subsequent cleavage and processing until it forms Aβ plaques. Assessment was carried out using human brain tissue samples collected from the cortex of a control group, MCI group, and AD group from the Kentucky Brain Bank, and included multiple experiments such as SYBR-Green chemistry-based quantitative real-time PCR for measurement of gene expression, ELISA for measurement of Aβ42/Aβ40 peptides and levels of phosphorylated tau, ATP production measured with an ATP determination kit, and finally, oxidative stress assay that measured H2O2 production and lipid peroxidation level. Results indicated phosphorylated tau levels progressively increased from control to MCI to AD. We also found decreased levels of ADAM10 and mitochondrial fusion genes (Mfn1, Mfn2, OPA) in MCI and AD groups in comparison with control, but increased levels in mitochondrial fission genes (DRP1, Fis1) and BACE1 in the AD group in comparison with control. Additionally, Aβ42 and soluble amyloid oligomer levels were higher in the AD group. Our data showed that mitochondrial dysfunction correlated with AD pathology (beta - amyloid, phosphorylated-Tau).
Audience Take Away
- Studying the effects of mitochondrial dysfunction on Alzheimers pathology will allow us to have a better understanding of the pathophysiology and can help further research in determining a treatment
- This project provides information on specific mitochondrial proteins and how they relate to ROS and ATP production, with its implications to Alzheimers only partially understood
- Mild cognitive impairment is a poorly defined intermediate pathology that we included in our study and compared it to a control and Alzheimers group. This helps further the knowledge on this disease state so it may one day be better characterized, and clinicians can incorporate it into their practices to aid in early diagnosis and management
