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.