A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission
| Autor: | Wen Yao, Luciano D'Adamio, Tao Yin, Kelly A Norris |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
imBRI2 immature BRI2 amyloid precursor protein Deafness Biochemistry Synaptic Transmission Amyloid beta-Protein Precursor PPF paired-pulse facilitation FBD familial British dementia Postsynaptic potential Amyloid precursor protein rat education.field_of_study Neurodegeneration neurodegeneration ITM2b integral membrane protein 2B NMDAR N-methyl-d-aspartic acid Receptors Glutamate Rs series resistance Excitatory postsynaptic potential amyloid β AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor Female AD Alzheimer's disease Research Article Aβ amyloid β Cerebellar Ataxia integral membrane protein 2B Neural facilitation Presynaptic Terminals glutamate Biology Cataract APP amyloid-β precursor protein Glutamatergic BRI2 Alzheimer Disease Memory medicine KI knock in Integral membrane protein 2B Animals mEPSC miniature excitatory postsynaptic current Excitatory Amino Acid Agents mBRI2 mature BRI2 education Molecular Biology NFT neurofibrillary tangle Adaptor Proteins Signal Transducing Amyloid beta-Peptides synaptic plasticity animal model Membrane Proteins Cell Biology familial Danish dementia medicine.disease Pr probability of release Rats Disease Models Animal SC Schaeffer-collateral Synaptic plasticity Synapses biology.protein ACSF artificial cerebrospinal fluid Dementia ISI interstimulus interval Neuroscience FDD familial Danish dementia |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-β precursor protein (APP), whose mutations cause familial forms of Alzheimer's disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid β (Aβ), a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles and produce human Aβ. Here, we studied young Itm2bD rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2bD rats not only present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia. |
| Databáze: | OpenAIRE |
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