levetiracetam and Amyloidosis

Cerebral amyloid β (Aβ) proteostasis is compromised under neuronal overexcitation, long-term neuroinflammation and brain aging. Using the animal model of LPS-induced neuroinflammation we demonstrated that treatment with levetiracetam, a specific modulator of synaptic vesicle glycoprotein SV2A, rescues abnormal synaptic vesicle (SV) fusion and neurotransmitter release, decreasing elevated hippocampal APP levels in vivo. Therapy with levetiracetam upregulates the SV2A in hippocampus and restores the level of apolipoprotein E, involved in brain Aβ aggregation/clearance and resolution of inflammation. We demonstrated that oligomers of Aβ

Topics: Amyloid beta-Peptides; Amyloidosis; Animals; Cells, Cultured; Drug Delivery Systems; Hippocampus; Levetiracetam; Lipopolysaccharides; Male; Membrane Glycoproteins; Nerve Tissue Proteins; Nootropic Agents; Peptide Fragments; Rats; Rats, Wistar

In recent years, aberrant neural oscillations in various cortical areas have emerged as a common physiological hallmark across mouse models of amyloid pathology and patients with Alzheimer's disease. However, much less is known about the underlying effect of amyloid pathology on single cell activity. Here, we used high-density silicon probe recordings from frontal cortex area of 9-month-old APP/PS1 mice to show that local field potential power in the theta and beta band is increased in transgenic animals, whereas single-cell firing rates, specifically of putative pyramidal cells, are significantly reduced. At the same time, these sparsely firing pyramidal cells phase-lock their spiking activity more strongly to the ongoing theta and beta rhythms. Furthermore, we demonstrated that the antiepileptic drug, levetiracetam, counteracts these effects by increasing pyramidal cell firing rates in APP/PS1 mice and uncoupling pyramidal cells and interneurons. Overall, our results highlight reduced firing rates of cortical pyramidal cells as a pathophysiological phenotype in APP/PS1 mice and indicate a potentially beneficial effect of acute levetiracetam treatment.

Topics: Action Potentials; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Disease Models, Animal; Frontal Lobe; Levetiracetam; Male; Mice, Transgenic; Presenilin-1; Pyramidal Cells