The -Secretase-Derived C-Terminal Fragment of APP, C99, But Not A , Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus

Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Team "Fondation pour la Recherche Médicale" and "Laboratoire d'Excellence Distalz," 06560 Sophia-Antipolis, France, Elan Pharmaceuticals, South San Francisco, California 94080, Cap Delta-Parc Euromédecine, CNRS UMR 3145, SysDiag, 34184 Montpellier, France, and Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S3H2, Canada.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2012; 32(46):16243-16255. DOI: 10.1523/JNEUROSCI.2775-12.2012
Source: PubMed

ABSTRACT Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated β-amyloid precursor protein (βAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-β peptides (Aβ) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aβ that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the β-secretase-derived βAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aβ is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aβ deposits are detected ∼12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the βAPP(swe) and Tau(P301L) mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest βAPP catabolite and main contributor to the intracellular βAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.

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