The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM.

The accumulation of neurotoxic amyloid-beta (Aß) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aß. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aß efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aß through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aß transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aß from the brain.

Anti-NMDA receptor encephalitis in a 73-year-old female with secondary progressive multiple sclerosis: A case report.

Anti-NMDA receptor (Anti-NMDAR) encephalitis is an autoimmune disease that presents with diverse symptoms. Since literature is scarce on the overlap with multiple sclerosis (MS), this report aims to elucidate the distinctive clinical presentation and diagnostic challenges of anti-NMDAR encephalitis in MS patients. A 73-year-old woman with secondary progressive multiple sclerosis, after experiencing status epilepticus and subsequent non-convulsive status epilepticus, presented with neuropsychiatric symptoms and autonomic nervous dysfunction. Notably, the patient had not received any immunomodulatory therapy. The clinical picture together with diagnostics (MRI, EEG, cerebro-spinal fluid) let us suspect HSV-meningoencephalitis and empirically treat the patient with IV acyclovir. Due to a lack of clinical improvement, we reconsidered the diagnosis and found the diagnostic criteria for autoimmune encephalitis to be met. Antibodies in blood and CSF were positive and we diagnosed the patient with anti-NMDAR encephalitis. The patient responded well to IV prednisolone treatment, leading to a stable outcome in a six-month follow-up. This case highlights the difficulties in diagnosing anti-NMDAR encephalitis in patients with multiple sclerosis. The presence of epileptic seizures can serve as a crucial diagnostic indicator to distinguish between an MS relapse and an overlapping disease. Compared to patients with other demyelinating diseases, patients with overlapping MS appear to have a higher risk of motor seizures.