ABSTRACT
The amyloid-ß precursor protein (APP) is a ubiquitous protein with a strong genetic link to Alzheimer's disease. Although the protein was identified more than forty years ago, its physiological function is still unclear. In recent years, advances in technology have allowed researchers to tackle APP functions in greater depth. In this review, we discuss the latest research pertaining to APP functions from development to aging. We also address the different roles that APP could play in specific types of cells of the central and peripheral nervous system and in other organs of the body. We argue that, until we fully identify the functions of APP in space and time, we will be missing important pieces of the puzzle to solve its pathological implication in Alzheimer's disease and beyond.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Humans , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Synapses/metabolism , Peripheral Nervous System/pathology , Amyloid beta-Peptides/metabolismABSTRACT
N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic-derived C-terminal fragments, rather than APP full-length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain. Interfering with stability or production of the APP intracellular domain normalized the GluN2B-NMDARs currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments.
Subject(s)
Amyloid beta-Protein Precursor , Receptors, N-Methyl-D-Aspartate , Mice , Humans , Animals , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction , Hippocampus/metabolism , Synapses/metabolismABSTRACT
Activation and sensitization of trigeminal ganglia (TG) sensory neurons, leading to the release of pro-inflammatory peptides such as calcitonin gene-related peptide (CGRP), are likely a key component in migraine-related headache induction. Reducing TG neuron excitability represents therefore an attractive alternative strategy to relieve migraine pain. Here by using pharmacology and genetic invalidation ex vivo and in vivo, we demonstrate that activating TREK1 and TREK2 two-pore-domain potassium (K2P) channels inhibits TG neuronal firing sufficiently to fully reverse the migraine-like phenotype induced by NO-donors in rodents. Finally, targeting TREK is as efficient as treatment with CGRP antagonists, which represents one of the most effective migraine therapies. Altogether, our results demonstrate that inhibiting TG excitability by pharmacological activation of TREK channels should be considered as an alternative to the current migraine treatment.
