Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 56, Issue 2, Pages 641-653Publisher
IOS PRESS
DOI: 10.3233/JAD-160806
Keywords
Alzheimer's disease; amyloid beta; beta-secretase; hippocampus; slice culture; synapse
Categories
Funding
- JSPS KAKENHI [26460707, 16H04667, 3300128, 26670127]
- Strategic Research Program for Brain Sciences (Developmentof biomarker candidates for social behavior) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- MEXT
- Foundation of Strategic Research Projects in Private Universities from MEXT [S1311011]
- Fugaku Trust for Medicinal Research
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17K09040, 26430059, 16H04667, 26670127, 26460707] Funding Source: KAKEN
Ask authors/readers for more resources
The amyloid-beta protein precursor (A beta PP) is cleaved by a transmembrane protease termed beta-site A beta PP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer's disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage. However, the effects of the inhibition of BACE1 activity on already developed neurons remain unclear. Here, we utilized hippocampal slice cultures as an ex vivo model that enabled continuous and long-term analysis for the effect of BACE1 inhibition on neuronal circuits and synapses. Temporal changes in synaptic proteins in hippocampal slices indicated acute synaptic loss, followed by synapse formation and maintenance phases. Long-term BACE1 inhibition in the neurodevelopmental stage caused the loss of synaptic proteins but failed to alter synaptic proteins in the already developed maintenance stage. These data indicate that BACE1 function on synapses is dependent on synaptic developmental stages, and our study provides a useful model to observe the long-term effect of BACE1 activity in the brain, and to evaluate adverse effects of BACE inhibitors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available