Inhibition of -secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia

Robert Tamayev, Luciano Dadamio

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid- precursor protein (APP) processing, which is genetically linked to Alzheimers disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by -secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDD KI). -cleavage of APP yields the -carboxyl-terminal (-CTF) and the amino-terminal-soluble APP (sAPP) fragments. -secretase processing of -CTF generates A, which is considered the main cause of AD. However, inhibiting A production did not rescue the deficits of FDD KI mice, suggesting that sAPP/-CTF, and not A, are the toxic species causing memory loss. Results: Here, we have further analyzed the effect of -secretase inhibition. We show that treatment with a -secretase inhibitor (GSI) results in a worsening of the memory deficits of FDD KI mice. This deleterious effect on memory correlates with increased levels of the /-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDD KI mice, which is consistent with inhibition of -secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for A, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic /-CTFs caused by GSI treatment. However, -secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other -secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting -secretase in the therapy of AD. Overall, the data also indicate that FDD KI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.

Original languageEnglish (US)
Article number19
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

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Amyloid Precursor Protein Secretases
Memory Disorders
Dementia
Amyloid beta-Protein Precursor
Alzheimer Disease
Poisons
N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
Mutation
Inhibition (Psychology)
Familial Danish dementia
Cognition
Hippocampus
Proteins
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Inhibition of -secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. / Tamayev, Robert; Dadamio, Luciano.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 19, 2012.

Research output: Contribution to journalArticle

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abstract = "Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid- precursor protein (APP) processing, which is genetically linked to Alzheimers disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by -secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDD KI). -cleavage of APP yields the -carboxyl-terminal (-CTF) and the amino-terminal-soluble APP (sAPP) fragments. -secretase processing of -CTF generates A, which is considered the main cause of AD. However, inhibiting A production did not rescue the deficits of FDD KI mice, suggesting that sAPP/-CTF, and not A, are the toxic species causing memory loss. Results: Here, we have further analyzed the effect of -secretase inhibition. We show that treatment with a -secretase inhibitor (GSI) results in a worsening of the memory deficits of FDD KI mice. This deleterious effect on memory correlates with increased levels of the /-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDD KI mice, which is consistent with inhibition of -secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for A, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic /-CTFs caused by GSI treatment. However, -secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other -secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting -secretase in the therapy of AD. Overall, the data also indicate that FDD KI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.",
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