Mitochondrial Protection in Glaucomatous Optic Neuropathy

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Alzheimer’s disease (AD) is one of the most prevalent and complex neurodegenerative diseases worldwide. Accumulating evidence indicates that AD is potentially linked to alterations of mitochondrial dynamics and function, indicating that mitochondrial dysfunction is a potential therapeutic target for AD intervention and treatment. However, no current therapies prevent the disease. A-kinase anchoring protein 1 (AKAP1) is an outer mitochondrial membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial network, bioenergetics and calcium homeostasis. Recently, our group has discovered that 1) loss of AKAP1 triggers mitochondrial fission dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation, deregulates oxidative phosphorylation, and induces metabolic and oxidative stress, 2) neuronal AKAP1 has potent neuroprotective properties by inhibiting DRP1, enhancing mitochondrial activity, and blocking apoptotic cell death. These results suggest the possibility that modulation of AKAP1 has therapeutic potential in mitochondrial dysfunction and neurodegeneration. Our preliminary data showed that 1) amyloid precursor protein (APP)/presnilin 1 (PS1) mutation induces a significant loss of AKAP1 and reduction of DRP S637 phosphorylation, 2) APP/PS1 mutation induces a significant reduction of optic atrophy type 1, 3) APP/PS1 mutation induces a significant reduction of peroxisome proliferator-activated receptor-gamma coactivator 1α and mitochondrial transcription factor A expression, and 4) APP/PS1 mutation induces an increase of BAX and BCL- xL expression in the retina of young APP/PS1 mice. Based on these findings, our proposal has two specific aims. In Aim 1, we will determine whether AKAP1 deficiency contributes to the impairment of mitochondrial bioenergetics and structure in AD retinal ganglion cells (RGCs). We will investigate structural and functional changes of mitochondria, mitophagosome formation in AD mice and test the effect of AKAP1 deficiency on mitochondrial dysfunction in RGCs and hippocampal neurons using AKAP1-/- APP/PS1 mice. In Aim 2, we will determine the protective effect of AKAP1 amplification on AD RGCs. We will investigate if AKAP1 amplification preserves mitochondrial structure and function and prevents dendritic arbor alteration and synaptic losses in APP/PS1 RGCs and hippocampal neurons. We anticipate that these studies will enhance our understanding of how AKAP1 regulates mitochondrial networks and functions in the early stage of AD pathogenesis. Also, this proposal will probe AKAP1 amplification as a strategy to induce neuroprotection in both the retina and brain against AD and related dementias.