Expression of human β‐secretase in the mouse brain increases the steady‐state level of β‐amyloid

Abstract

b-Site APP-cleaving enzyme (BACE) initiates the processing of the amyloid precursor protein (APP) leading to the generation of b-amyloid, the main component of Alzheimer's disease senile plaques. BACE (Asp2, memapsin 2) is a type I transmembrane aspartyl protease and is responsible for the b-secretase cleavage of APP producing different endoproteolytic fragments referred to as the carboxy-terminal C99, C89 and the soluble ectodomain sAPPb. Here we describe two transgenic mouse lines expressing human BACE in the brain. Overexpression of BACE augments the amyloidogenic processing of APP as demonstrated by decreased levels of full-length APP and increased levels of C99 and C89 in vivo. In mice expressing huBACE in addition to human APP wild-type or carrying the Swedish mutation, the induction of APP processing characterized by elevated C99, C89 and sAPPb, results in increased brain levels of b-amyloid peptides Ab40 and Ab42 at steady-state.

PAR-4 Is Involved in Regulation of β-Secretase Cleavage of the Alzheimer Amyloid Precursor Protein

“…The observation that mice with a targeted deletion of BACE1 are viable and fertile but fail to produce any A␤ indicates that BACE1 is strictly required for A␤ generation and that inhibition of BACE1 activity might be a safe and effective treatment option for AD (6,40,51,62). Because the increased BACE1 activity observed in AD patients does not seem to arise from genetic mutations or polymorphisms in BACE1 (1,42,47,51), the identification of factors that effectively regulate BACE1 activity is apparently a highly promising approach to treating AD. PAR-4 is a leucine zipper protein that was initially identified to be associated with neuronal degeneration in AD (94).…”

“…The observation that mice with a targeted deletion of BACE1 are viable and fertile but fail to produce any A␤ indicates that BACE1 is required for A␤ generation (6,40,51,62). Because neither genetic mutations nor polymorphisms in BACE1 seem to be responsible for the increased BACE1 activity observed in AD patients (1,42,47,51), the identification of factors that effectively regulate BACE1 activity is apparently a highly promising approach to treating AD.…”

“…Cleavage of CTF99 by ␥-secretase produces A␤ . In vitro, BACE1 was shown to be able to generate two APP C-terminal fragments (CTFs) starting at either Asp 1 (CTF99) or Glu 11 (CTF89) of the A␤ sequence (47,49). Alternatively, cleavage of APP at the ␣-secretase site generates a soluble N-terminal fragment (soluble APP␣) and leaves the C-terminal fragment (known as CTF83) containing the APP transmembrane domain and cytoplasmic tail (89 -93).…”

“…Mature BACE1 is formed when cleaved immature BACE1 is further modified by N-linked glycosylation (46,55,57,66). BACE1 mRNA is found in neurons of all brain regions (47,64,72). Cleavage of APP by ␤-secretase (BACE1) generates a soluble N-terminal fragment (soluble APP␤) and a membrane-bound C-terminal fragment (known as CTF99).…”

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

“…With the identification of BACE1 [36,37,40], it was determined that β-secretase cleavage can be, in fact, the rate-limiting event for Aβ production. In addition, overexpression of BACE1 in APP transgenic mice results in increased β-secretase cleavage products particularly increased Aβ levels [2,4,28] as well as altered amyloid deposition pathology [4,28,38]. Specifically, we have previously reported an altered brainregional deposition profile in our double BACE1xAPP transgenic mice.…”