Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer's disease (AD) pathogenesis involves the amyloidogenic pathway, initiated by beta-secretase (BACE) cleavage of amyloid precursor protein (APP).
• Understanding the role of BACE in beta-amyloid (Abeta) plaque formation is crucial for AD research.

Purpose of the Study:

• To investigate the sufficiency of BACE overexpression in inducing Abeta plaque formation.
• To examine the combined effect of BACE and Swedish mutation of APP (SwAPP) on AD-like pathology in transgenic mice.

Main Methods:

• Generation of transgenic mice expressing neuronal BACE.
• Generation of double transgenic mice co-expressing neuronal BACE and SwAPP.
• Histopathological analysis and Abeta level assessment in transgenic mice at various ages.

Main Results:

• Single transgenic mice overexpressing BACE did not develop extracellular beta-amyloid plaques by 14 months but showed intracellular Abeta.
• Double transgenic mice (BACE + SwAPP) exhibited accelerated AD-like pathology, including early extracellular Abeta deposition and reactive astrocytes at two months.
• Well-defined beta-amyloid deposits surrounded by activated astrocytes were evident in double transgenic mice by four months.

Conclusions:

• BACE overexpression alone is insufficient to cause beta-amyloid plaque formation.
• Simultaneous expression of BACE and its substrate SwAPP significantly accelerates amyloid plaque formation and AD pathology.
• This study highlights the critical interplay between BACE activity and APP processing in driving AD neuropathology.