ausblenden:
Schlagwörter:
Alzheimer Disease/*genetics/pathology
Amyloid beta-Peptides/genetics
Animals
Behavior, Animal
CCAAT-Enhancer-Binding Protein-beta/*genetics
Drosophila Proteins/*genetics
Drosophila melanogaster/genetics
Excitatory Amino Acid Agents
Humans
Monomeric Clathrin Assembly Proteins/genetics
Nerve Tissue Proteins/genetics
Peptide Fragments/genetics
Receptors, Ionotropic Glutamate/*genetics
Synaptic Transmission/genetics
Transcription Factors/*genetics
Vesicular Glutamate Transport Proteins/*genetics
Zusammenfassung:
Alzheimer's disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome-wide association studies have linked PICALM to AD risk. PICALM has been implicated in Abeta42 production and turnover, but whether it plays a direct role in modulating Abeta42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue Abeta42 toxicity in an adult-onset model of AD, without affecting Abeta42 level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation, have been associated with AD. We found that Abeta42 caused the accumulation of presynaptic vesicular glutamate transporter (VGlut) and increased spontaneous glutamate release. Increased lap expression reversed these phenotypes back to control levels, suggesting that lap may modulate glutamatergic transmission. We also found that lap modulated the localization of amphiphysin (Amph), the homologue of another AD risk factor BIN1, and that Amph itself modulated postsynaptic glutamate receptor (GluRII) localization. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.
