Levetiracetam Alleviates Cognitive Decline in Alzheimer’s Disease Animal Model by Ameliorating the Dysfunction of the Neuronal Network

Abstract Patients with Alzheimer’s disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)—a drug for treating seizures—on learning and memory and neuropathological features of AD. We bred APP23 mice with MAPT transgenic mice to generate APP23/MAPT mice. These were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. The results revealed that low, but not high concentrations of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low concentrations of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of Aβ by reducing the expression of β site APP cleavage enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement abilities in mice, and did not improve cognitive decline in AD mice. Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. Low, but not high concentration of LEV may help ameliorate abnormalities in people who have or are at risk of AD.