Synaptic Profile and Oxidative Stress Associated with Amyloid-β in the Hippocampus
Authors: Ramsey Jax , Schodl Thomas , Chimienti Katelyn , Han Byunghee , Ostrowski Daniela , Ostrowski Tim 
Published: May 2024

Alzheimer’s Disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. The neuropathology is mainly due to disturbances in neuronal circuits and protein aggregations of phosphorylated tau and Amyloid-β (Aβ). Other factors found in disease progression are oxidative stress, microglial activation, and decreased synaptic transmission. However, it is unknown whether these changes occur only in close association with Aβ plaques, or rather have broad occurrence throughout memory-related brain structures. Thus, we analyzed synaptic markers, glial cells, and oxidative stress in the memory associated CA1 hippocampal region of APP/PS1 transgenic mice. Specifically, we assessed these targets in the immediate vicinity and distant from Aβ plaques. Hippocampal sections (coronal, 30 μm thick) from 1-year-old APP/PS1 mice and their wild type controls (n = 6/group) were fluorescently labeled for synapse density (synaptophysin), vesicular glutamate transporter (vGLUT2), DNA oxidation (8-hydroxyguanosine, 8-OHG), microglia (Iba-1), astrocytes (GFAP), neurons (NeuN), and Aβ plaques (X-34). Images were taken in the CA1 region with a conventional fluorescent microscope and analyzed using ImageJ. Fluorescence intensity was then quantified for each group. Next, the intensity profile was plotted for each fluorophore across the width of the Aβ plaques. There were relatively few amyloid plaques in the hippocampal CA1 region of APP/PS1 mice when compared to other regions of the hippocampus and cerebral cortex. Within the CA1 region, and in absence of Aβ, there was no pronounced change in synaptic density, presynaptic glutamate transporters, neurons, DNA oxidation, astrocytes, or microglia when compared to wild-type control. However, fluorescent intensity of some targets changed markedly along the perimeter of occasionally occurring Aβ plaques in the CA1 region. While the intensity profile of synaptophysin declined gradually towards the center of Aβ plaques, oxidative stress and microglia increased in the immediate surroundings of Aβ. Unexpectedly, also the intensity of presynaptic glutamate transporter vGLUT2 increased towards the core of the Aβ plaque. In summary, our data showed increased vesicular glutamate transporter, microglia, and oxidative stress confined to the vicinity of Aβ plaques in APP/PS1 mice. Increased vGLUT2 levels due to Aβ have been previously associated with hyperexcitability in AD. The parallel or subsequent decrease in synaptophysin is viewed as a compensatory response to limit hyperactivity. Together, the present study reveals important insights about the dynamics of cellular components in the vicinity of Aβ, and that aggregates of Aβ differentially affect presynaptic components important for synaptic transmission. NIH R15AG065927 (TDO & DO), Truman State GIASR grant (TS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.