BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

Abstract

Alzheimer disease (AD) is characterized by senile plaques, which are mainly composed of ␤ amyloid (A␤) peptides. A␤ is cleaved off from amyloid precursor protein (APP) with consecutive proteolytic processing: ␤-secretase, followed by ␥-secretase. Here, we show that BRI3, a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2, interacts with APP and serves as an endogenous negative regulator of A␤ production. BRI3 colocalizes with APP along neuritis in differentiated N2a cells; endogenous BRI3-APP complexes are readily detectable in mouse brain extract; reducing endogenous BRI3 levels by RNA interference results in increased A␤ secretion. BRI3 resembles BRI2, because BRI3 overexpression reduces both ␣-and ␤-APP cleavage. We propose that BRI3 inhibits the various processing of APP by blocking the access of ␣-and ␤-secretases to APP. However, unlike BRI2, the binding of BRI3 to the ␤-secretase cleaved APP C-terminal fragment is negligible and BRI3 does not cause the massive accumulation of this APP fragment, suggesting that, unlike BRI2, BRI3 is a poor ␥-cleavage inhibitor. Competitive inhibition of APP processing by BRI3 may provide a new approach to AD therapy and prevention.About 1% of humans aged 60 -64 years have AD, 2 increasing steadily to as many as 35-40% after age 85 (1). AD progressively leads to a severely impaired state and complete social dependence. At autopsy, cerebral atrophy, neurofibrillary tangles, and amyloid plaques are observed in the hippocampus, entorhinal cortex, amygdala, and other areas. Tangles consist of intraneuronal masses of helically wound filaments of the hyperphosphorylated protein, Tau. Plaques are extracellular deposits of A␤, a peptide derived from cleavage of APP, surrounded by dystrophic neurites. Most AD cases present A␤ deposits in cortical and/or meningeal microvessels. In a minority of cases, this vascular cerebral amyloid angiopathy is rather severe (2).APP is a type I transmembrane protein that undergoes a series of proteolytic cleavages (3). ␤-Secretase cleaves APP into a soluble ectodomain (sAPP␤) and a membrane-bound C-terminal fragment of 99 amino acids (C99). C99 is cleaved by the ␥-secretase, which consists of a multicomponent complex composed of presenilins (PS1 and PS2), Nicastrin, PEN2, and APH1 (4). The ␥-cleavage releases two peptides: A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively) and an intracellular product APP intracellular domain (AID)/AICD. Several findings point to the short AID/AICD as a biologically active intracellular peptide, which may modulate cell death, Notch signaling, gene transcription, and Ca 2ϩ homeostasis (5-19). In an alternative pathway, APP is processed by ␣-secretase within the A␤ sequence, leading to the production of the soluble sAPP␣ ectodomain and a membrane-bound C-terminal fragment of 83 amino acids (C83). For aged patients, a family history of dementia is a major risk factor for AD, and 10 -15% of all AD subjects have a family history c...

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

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Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

“…In contrast, mutations in APP and in genes that regulate APP processing, such as PSENs and BRI2/ITM2B, cause familial dementias (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). APP is cleaved by ␤-secretase/BACE1 into a soluble ectodomain (soluble APP␤) and the COOH-terminal fragment ␤-CTF.…”

Anti-amyloidogenic property of human gastrokine 1

“…It was shown that the dementia gene BRI2 was an inhibitor of APP processing [29,30] and that BRI3, a member of the same gene family, was able to bind APP and to inhibit the production of Ab [31]. BRI gene family products that comprise also BRI1, are type II transmembrane (TM) proteins containing a BRICHOS domain.…”