Recently, BACE1 expression was shown to be regulated by microRNAs, small endogenous RNA molecules that regulate protein expression through sequence-specific interaction with messenger RNA. Here, we showed that microRNA-29c (miR-29c), a miRNA that is enriched in the brain and highly expressed in the APPswe/PSΔE9 mouse lowers BACE1 protein in vitro and in transgenic miR-29c mice. In silico analysis identified two putative target sites in the BACE1 mRNA for the miR-29c family. We chose SH-SY5Y, HEK-293T cell lines and miR-29c transgenic mice for these studies to validate our hypothesis. Significantly, over-expression of miR-29c in SH-SY5Y, HEK-293T cell lines and miR-29c transgenic mice downregulated BACE1 protein levels. Our findings suggest that miR-29c may be an endogenous regulator of BACE1 protein expression.