Dr. Heather Wilkins, University of Kansas Medical Center<\/strong><\/p>\n April 23, 2020<\/p>\n Dr. Wilkins began by reviewing the \u201cAmlyoid Cascade\u201d and the \u201cPhosphorylated Tau\u201d theories of Alzheimer\u2019s disease (AD), noting their similarities.\u00a0 She is, however, most interested in a third theory, called the \u201cMitochondrial Hypothesis\u201d which posits that mitochondrial dysfunction is the first step in the development of Alzheimer\u2019s Disease.\u00a0 She proposed that mitochondrial dysfunction eventually leads to the aggregation of AB and p-tau.\u00a0 While mitochondrial dysfunction is commonly caused by normal aging, Dr. Wilkins suggested that this occurs more rapidly in those predisposed to AD.<\/p>\n Today she focused on the association between mitochondrial dysfunction and the accumulation of A\u03b2.<\/p>\n She reviewed the processes by which the amyloid precursor protein (APP) is cleaved to form peptide fragments by the various secretase enzymes to generate A\u03b2 chains of various length (with A\u03b2 40<\/sub> and 42<\/sub> being the most commonly studied).\u00a0 She also reviewed the \u201ctimeline of discovery\u201d to note how our understanding of these processes has improved relatively recently.<\/p>\n These resources are available at: http:\/\/kualzheimer.org\/<\/a><\/p>\n Dr. Wilkins explored the evidence that AD is primarily a problem with mitochondrial energy metabolism.<\/strong><\/p>\n She noted, as support for this view, that AD pathology is associated with increases in mitochondrial DNA (mtDNA) mutations and deletions; a reduction in components of the electron transport chain, including cytochrome C oxidase (Complex IV); decreased glucose uptake and metabolism; and the presence of older, malfunctioning mitochondria.<\/p>\n Her work focuses specifically on the importance of the mitochondrial membrane potential.<\/p>\n A reminder for non-experts:<\/strong> mitochondria, often called the \u201cpowerhouse\u201d of the cell produce ATP and other forms of useful stored energy by burning fuels such as sugars and fats.<\/p>\n Mitochondria act much like a battery, separating + and – electrical charges. This separation of charge occurs across the mitochondrial membrane.\u00a0 It separats two compartments – the internal space (the matrix; with a net negative charge) and external space (the intermembrane space, with a net positive charge).\u00a0 The burning (\u201coxidation\u201d) of fuels provides the power to charge the \u201cmitochondrial battery\u201d. \u00a0A fully charged mitochondria has an electrical potential of about 0.1 volts. \u00a0When the two compartments are connected, the flow of protons (positively charged ions) powers the production of ATP.<\/p>\n In general, young mitochondria are superior for producing high amounts of ATP while minimizing the production of toxic byproducts, e.g. reactive oxygen species (ROS).<\/p>\n Dr. Wilkins proposed that the mitochondria membrane potential \u2013 specifically those that are too low (hypopolarization) or too high (hyperpolarization) – is linked to the amount of A\u03b2 that accumulates in cells.<\/p>\n To test this, she studies SY5Y neuroblastoma cells, including mutant cell lines that lack key components of the mitochondrial \u201cbattery\u201d. \u00a0She also studies the impacts of drugs which change the polarization of mitochondrial membranes, such as FCCP which causes hypopolarization and oligomycin which causes hyperpolarization.<\/p>\n She observes that:<\/p>\n In general Dr. Wilkins observes that the mitochondrial membrane potential is positively correlated with the accumulation of A<\/strong>\u03b242<\/sub>. <\/strong><\/p>\n She expanded this work to examine the response of neurons developed from stem cells (iPSCs) of patients confirmed to have had Alzheimer\u2019s disease.\u00a0 The mitochondria of iPSCs from older AD patients did not exhibit altered mitochondrial membrane potentials but, interesting, those from younger patients did.<\/p>\n She then pivoted to discuss a theory called \u201cMAGIC: Mitochondria As Guardians In the Cytoplasm\u201d, described here:<\/p>\n Fang, E.F., Hou, Y., Palikaras, K. et al. Mitophagy inhibits amyloid-\u03b2 and tau pathology and reverses cognitive deficits in models of Alzheimer\u2019s disease. Nat Neurosci 22, 401\u2013412 (2019). https:\/\/doi.org\/10.1038\/s41593-018-0332-9<\/a><\/p>\n This study showed that the recycling of old, poorly functioning mitochondria (\u201cmitophagy\u201d) is inhibited in AD.\u00a0 Those authors conclude: Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.\u201d<\/p>\n This theory emphasizes the importance of recycling old mitochondria to maintain efficient ATP production, without generating toxic byproducts.\u00a0 This strategy has been proposed to address a range of neurodegenerative disorders, as highlighted by a fun paper we sometimes discuss in class:<\/p>\n Komen JC, Thorburn DR. Turn up the power – pharmacological activation of mitochondrial biogenesis in mouse models. Br J Pharmacol. 2014;171(8):1818\u20131836. doi:10.1111\/bph.12413<\/p>\n
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