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Abstract
A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ.
Highlights
Amyloid deposition of amyloid-b (Ab) peptide characterises Alzheimer disease (AD)
The BRI2 domain that binds amyloid-b precursor protein (APP) and inhibits APP processing maps to amino acids 74–102 To test if the loss of mature BRI2 (mBRI2) in familial Danish dementia (FDD) impairs memory via toxic APP metabolites resulting from processing, we searched for BRI2-derived peptides that replicate the inhibitory function of BRI2 on APP-cleavage. mBRI2 interacts with mature APP and bcarboxyl-terminal fragments (b-CTF), and increases the levels of b-carboxyl-terminal fragments (b-CTF) by inhibiting its g-cleavage (Matsuda et al, 2005; Matsuda et al, 2008; Fig 1B and C)
The levels of a-Tubulin were similar in all transfected cells and a-Tubulin was not precipitated by antimyc, further underlying the specificity of the mBRI2/mAPP interaction
Summary
Ab derives from sequential cleavage of amyloid-b precursor protein (APP) by b- and g-secretases (Cole & Vassar, 2007; De Strooper et al, 2010; Fig 1A). In normal individuals the immature BRI2 precursor (imBRI2) is cleaved by convertases in the Golgi into mature BRI2 (mBRI2) and a carboxy-terminal 23 amino acid peptide (Bri). In the Danish kindred, the presence of a 10-nt duplication one codon before the normal stop codon produces a frame-shift in the BRI2 sequence generating a larger-than-normal precursor protein called BRI2ADan. Cleavage by convertases releases the amyloid subunit that comprises the last 34 COOH-terminal amino acids (ADan) and mBRI2. ADan accumulates into amyloid plaques, which contain both Ab and ADan (Choi et al, 2004; Vidal et al, 2000)
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