At the crossroads of epilepsy and Alzheimer's disease Investigating the role of LRP1 in the cerebral vasculature

There is increasing evidence that people with epilepsy have an increased risk of developing Alzheimer’s disease (AD). Epilepsy is also relatively more common in people with AD. Epileptiform activity may even accelerate the progression of AD. Therefore, managing epileptiform activity is crucial. However, a significant proportion of patients do not achieve seizure freedom following anti-seizure medications. Understanding underlying neurobiological mechanisms is essential for developing of new therapies. Accumulation of amyloid beta (Aβ) in the brain, a neuropathological hallmark of AD, has been observed in (a subset of) patients with epilepsy. In this thesis, we investigated the role of low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional transmembrane receptor involved in many physiological processes, including the clearance of brain Aβ via the blood-brain barrier (BBB). LRP1 expression in brain capillaries diminishes during aging and in AD. In this thesis, we show that LRP1 is downregulated at the BBB in both experimental epilepsy and patients with epilepsy. Furthermore, inducible knockout of brain endothelial LRP1 in transgenic mice leads to epileptiform activity and cognitive dysfunction associated with gliosis rather than brain Aβ accumulation or the increase of its soluble form. Future research should focus on therapeutic strategies aimed at preventing or restoring the loss of brain endothelial LRP1, potentially reducing epilepsy and cognitive decline.