Dissecting the Molecular Link Between Stroke, Actin, and Alzheimer's Disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, posing a grave socioeconomic burden on the elderly population. Studies have shown a strong increase in the risk of developing dementia after the occurrence of a stroke. Following a stroke, surviving neurons undergo numerous challenges, such as neuroinflammation, endoplasmic reticulum (ER) stress, and cytoskeletal rearrangements. These cellular processes are also characteristics of neurodegenerative diseases such as AD, suggesting overlapping cellular and molecular mechanisms in both stroke and AD that lead to negative neuronal outcomes. However, there remains a knowledge gap in understanding how early and transient molecular events occurring after acute hypoxia and glucose deprivation cause long lasting neuronal damage that leads to AD-like neurodegeneration. We hypothesize that ischemia-induced transient changes in the actin cytoskeleton homeostasis have long-term impacts on the structure and/or function of the nucleus, nuclear lamina, and nuclear pore via the activation of mechanosensitive pathways, affecting neuronal health and survival. Supporting this hypothesis, we and others have found that drastic alterations to actin homeostasis alters the integrity of the nuclear pore complex (NPC), a structure that has been implicated in the degenerative pathway of many neurodegenerative diseases, including AD. NPCs are connected to the cytoskeleton via the linker of nucleoskeleton and cytoskeleton (LINC) complex, which relays mechanical tension from the extracellular matrix and cytoskeleton to the nucleus and DNA. Our aims are as followed: Aim 1: Does IRI cause nuclear injury via mechanosensitive pathways in iPSC-derived hCNs? We hypothesize that ischemia-induced cytoskeletal rearrangements lead to long lasting alterations in functional stability of the nuclear lamina, NPC, and chromatin structure via the mechanosensitive pathways. We will use induced pluripotent stem cell (iPSC)-derived neurons exposed to ischemic stress to determine the mechanistic connection between actin rearrangements, mechanical tension via the LINC complex, and NPC integrity. Aim 2: Do IRI-induced cytoskeletal alterations impact neuronal resilience to stress? We hypothesize that ischemia-induced changes to the NPC and chromatin reduce neuronal resilience to age-related stressors, leading to premature degeneration. Using iPSC-derived neurons, we will determine to what extent ischemic stress alters neuronal transcriptional regulation leading to a reduced resilience to normal age-related stressors. At the end of this proposed research, we will have determined the fundamental cellular and molecular mechanisms that regulate long-term neuronal survival after an ischemic stroke. These novel insights will provide the necessary foundations for future studies using in vivo models of stroke and AD, thus opening the way for the identification of new potential therapeutic targets and biomarkers for both improving stroke outcomes and for early AD diagnosis and intervention.