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β-secretase inhibition prevents structural spine plasticity deficits in AppNL-G-F mice

Summary

Researchers tested whether a drug that blocks BACE1 (an enzyme involved in Alzheimer’s disease) could protect nerve cell connections in a mouse model of Alzheimer’s disease. They found that at high doses, the drug significantly improved the formation of new dendritic spines (connection points between neurons) and restored synaptic activity to near-normal levels. These findings suggest that using BACE1 inhibitors early in Alzheimer’s disease development, before widespread neuronal damage occurs, might help prevent cognitive decline.

Background

BACE1 inhibitors have failed in clinical trials for Alzheimer’s disease due to cognitive worsening, but preclinical evidence suggests they could be effective preventive treatments if applied before amyloid-beta accumulation. Previous studies show BACE1 inhibition reduces dendritic spine density in wild-type mice, though effects may differ in Alzheimer’s disease models.

Objective

To investigate dose-dependent effects of BACE1 inhibition on hippocampal dendritic spine dynamics in an APP knock-in mouse model at an early disease stage before irreversible synaptic loss occurs.

Results

AppNL-G-F mice showed impaired structural spine plasticity with reduced formation and loss of spines despite normal total spine density. High-dose NB-360 treatment significantly enhanced spine formation, increasing spine turnover rate to levels comparable to wild-type controls. Low-dose treatment had no effect in APP knock-in mice but increased spine stability in wild-type mice.

Conclusion

Early BACE1 inhibition with high-dose NB-360 could arrest pathological progression by improving dendritic spine dynamics in early Alzheimer’s disease stages before irreversible neuronal damage occurs. Primary preventive BACE1 inhibitor intervention may be beneficial if applied prior to substantial amyloid-beta accumulation and synaptic loss.
  • Published in:Frontiers in Aging Neuroscience,
  • Study Type:Preclinical Animal Study,
  • Source: PMID: 35936777, DOI: 10.3389/fnagi.2022.909586
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