Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.

The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.

Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye.

The extracellular matrix (ECM) is a biological substrate composed of collagens, proteoglycans and glycoproteins that ensures proper cell migration and adhesion and keeps the cell architecture intact. The regulation of the ECM composition is a vital process strictly controlled by, among others, proteases, growth factors and adhesion receptors. As it appears, ECM remodeling is also essential for proper neuronal and glial development and the establishment of adequate synaptic signaling. Hence, disturbances in ECM functioning are often present in neurodegenerative diseases like Alzheimer's disease. Moreover, mutations in ECM molecules are found in some forms of epilepsy and malfunctioning of ECM-related genes and pathways can be seen in, for example, cancer or ischemic injury. Low density lipoprotein receptor-related protein 1 (Lrp1) is a member of the low density lipoprotein receptor family. Lrp1 is involved not only in ligand uptake, receptor mediated endocytosis and lipoprotein transport-functions shared by low density lipoprotein receptor family members-but also regulates cell surface protease activity, controls cellular entry and binding of toxins and viruses, protects against atherosclerosis and acts on many cell signaling pathways. Given the plethora of functions, it is not surprising that Lrp1 also impacts the ECM and is involved in its remodeling. This review focuses on the role of Lrp1 and some of its major ligands on ECM function. Specifically, interactions with two Lrp1 ligands, integrins and tissue plasminogen activator are described in more detail.

Detection of Protein Uptake in In Vitro Cultured Astrocytes Exemplified by the Uptake of the Serine Protease, Tissue Plasminogen Activator.

Astrocytes are heterogeneous cells of the central nervous system whose uptake of neurotransmitters and neuromodulators can influence synaptic signaling. Any malfunction in this process can lead to serious defects in synaptic transmission found in, for example, neurodegenerative diseases like Alzheimer's or epilepsy.Here we describe how to visualize the uptake of an extracellularly located protein by in vitro cultured astrocytes on the example of tissue plasminogen activator, a serine protease tightly involved in long-term potentiation and seizure generation.