BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Abeta) peptide formation.
• Abeta is generated by cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1).
• Inhibiting BACE1 is a proposed therapeutic strategy for AD.

Purpose of the Study:

• To evaluate the long-term physiological impact of chronic Abeta deficiency.
• To assess gene expression and phenotypic changes in older BACE1 knockout (KO) mice.
• To determine if Abeta deficiency affects neural gene expression or causes structural abnormalities.

Main Methods:

• Gene expression profiling of young BACE1 KO mice.
• Phenotypic assessment of BACE1 KO mice up to 14 months of age.
• Analysis of aged BACE1 KO mice overexpressing human APP (BACE1 KO/APPtg).

Main Results:

• No global compensatory changes in neural gene expression were detected in young BACE1 KO mice.
• BACE2 expression was not upregulated in BACE1 KO mice.
• No structural alterations were observed in any organ, including neural tissues, of BACE1 KO mice up to 14 months.
• Aged BACE1 KO/APPtg mice did not develop amyloid plaques.

Conclusions:

• Beta-secretase (BACE1) and Abeta do not play a vital role in mouse physiology.
• Chronic BACE1 inhibition may be a viable therapeutic approach for Alzheimer's disease.
• The absence of Abeta does not lead to compensatory upregulation of BACE2 or adverse physiological effects.