title: BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time.
abstract: The formation of Alzheimer's Abeta peptide is initiated when the amyloid precursor protein (APP) is cleaved by the enzyme beta-secretase (BACE1); inhibition of this cleavage has been proposed as a means of treating Alzheimer's disease. (AD) We have previously shown that young BACE1 knockout mice (BACE1 KO) do not generate Abeta but in other respects appear normal. Here we have extended this analysis to include both gene expression profiling and phenotypic assessment of older BACE1 KO animals to evaluate the impact of chronic Abeta deficiency. We did not detect global compensatory changes in neural gene expression in young BACE1 KO mice. In particular, expression of the beta-secretase homolog BACE2 was not upregulated. Furthermore, we found no structural alterations in any organ, including all central and peripheral neural tissues, of BACE1 KO mice up to 14 months of age. Aged BACE1 KO mice engineered to overexpress human APP (BACE1 KO/APPtg) did not develop amyloid plaques. These data provide evidence that neither beta-secretase nor Abeta plays a vital role in mouse physiology and that chronic beta-secretase inhibition could be a useful approach in treating AD.
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D010450:Endopeptidases; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse