Author(s)
Callie Hollander (student)1
Xiao-lei Zhang MD PhD1
Melinee D'Silva PhD2
Jerry Nadler MD2
Patric K. Stanton PhD (faculty)1
Affiliation(s)
1Department of Cell Biology, New York Medical College, Valhalla, NY 2Department of Pharmacology, New York Medical College, Valhalla, NY;
Abstract:
The relationship between cholesterol and cognitive decline remains an area of ongoing debate. However, elevated serum cholesterol is a risk factor for disorders associated with memory impairment, including Alzheimer’s disease (AD), vascular dementia (VaD), and Type 2 diabetes mellitus (T2DM). Although the underlying cellular mechanisms of these disorders remain unclear, high cholesterol induces vascular and inflammatory changes that disrupt the blood-brain barrier, damage neurons, and promote plaque formation—factors that may drive the pathogenesis of these disorders. As part of this process, the cytokine interleukin-12 activates STAT4, an inflammatory transcription factor that upregulates pro-inflammatory genes and facilitates T-helper 1 cell differentiation. These processes may contribute to neuroinflammation, which can disrupt synaptic plasticity and impair the mechanisms of memory storage in the brain. To investigate how elevated cholesterol and STAT4 activation affect long-term memory storage, we used electrophysiology techniques to measure two forms of activity-dependent long-term synaptic plasticity: long-term potentiation (LTP), the sustained strengthening of synapses following high-frequency stimulation, and long-term depression (LTD), the weakening of synapses in response to low-frequency stimulation. We measured LTP and LTD between CA3-CA1 synapses following Schaffer collateral stimulation in hippocampal slices from 24-week-old low-density lipoprotein receptor knockout (LDLr-/-) mice. These mice were fed either a standard diet or a high-fat, high-cholesterol diet (HFD-C) for 16 weeks, which significantly increases serum cholesterol levels. Subsequently, we examined whether reducing STAT4 activation could protect against synaptic plasticity impairments by comparing these LDLr-/- mice to genetically modified mice with a 50% reduction in activated STAT4 in both myeloid cells and neurons. Our results demonstrate that elevated serum cholesterol significantly impairs both LTP and LTD in LDLr-/- mice, with LTP deficits consistent across sexes and LTD deficits exhibiting sex differences. Notably, reducing STAT4 activation preserved synaptic plasticity, protecting both male and female mice from HFD-C-induced impairments in LTP and LTD. These findings suggest that STAT4 plays a crucial role in mediating synaptic plasticity deficits induced by a prolonged HFD-C and that suppressing STAT4 activation may provide a protective mechanism against cholesterol-induced memory impairment, potentially reducing the risk of cognitive decline in conditions such as AD, VaD, and T2DM.