Konings, S. C. | Search bioRxiv

bioRxiv2022

Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer's disease

The proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimers disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (A{beta}) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and A{beta}-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and A{beta}. To examine the individual roles of APP and A{beta} in promoting hyperexcitability we used an APP construct that does not generate A{beta}, or elevated A{beta} levels independently of APP. Increasing either APP or A{beta} in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we present evidence that both APP and A{beta} influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.

neuroscience↗

bioRxiv2020

APOE4 affects basal and NMDAR mediated protein synthesis in neurons by perturbing calcium homeostasis

Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans - APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimers disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons to APOE4 leads to a significant decrease in global protein synthesis. APOE4 treatment also abrogates the NMDA mediated translation response indicating an impairment of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure to APOE3 causes a short burst of calcium through NMDARs in neurons leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-VGCCs, thereby causing sustained translation inhibition through eEF2 phosphorylation, which in turn disrupts NMDAR response. Thus, we show that APOE4 affects basal and activity mediated protein synthesis response in neurons by affecting calcium homeostasis. We propose this as a possible mechanism to explain the synaptic dysfunction caused by APOE4. Highlights / SummaryO_LIAPOE3 treatment causes a short burst of calcium through NMDARs, leading to an acute increase in eEF2 phosphorylation which eventually recovers to basal levels. C_LIO_LIGlobal translation follows a similar temporal profile of initial inhibition followed by recovery in APOE3 treated neurons, thus unaffecting the NMDA mediated translation response. C_LIO_LIAPOE4 treatment activates both NMDARs and L-VGCCs leading to a marked elevation in calcium levels, thus causing sustained increase in eEF2 phosphorylation as well as global translation inhibition. C_LIO_LIHence, the NMDA mediated response is perturbed, potentially causing a stress-related phenotype in APOE4 treated neurons. C_LIO_LIThus, different calcium signatures and sources lead to distinct temporal profiles of translation. C_LI

neuroscience↗