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

I. Lauritzen (1) , R. Pardossi-Piquard (1) , C. Bauer (1) , E. Brigham , J.-D. Abraham , S. Ranaldi , P. Fraser , P. St-George-Hyslop , O. Le Thuc (1) , V. Espin (1) , L. Chami (1) , J. Dunys (1) , F. Checler (1)

1 IPMC - Institut de pharmacologie moléculaire et cellulaire

Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated ␤-amyloid precursor protein (␤APP swe), P310L-Tau (Tau P301L), and physiological levels of M146V-presenilin-1 (PS1 M146V) display extracellular amyloid-␤ peptides (A␤) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal A␤ 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 ␤-secretase-derived ␤APP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of ␥-secretase. Notably, intracellular A␤ is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular A␤ deposits are detected ϳ12 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 ␤APP 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 ␥-secretase. Together, our work identifies C99 as the earliest ␤APP catabolite and main contributor to the intracellular ␤APP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.

Domaines: Sciences du Vivant [q-bio]; Neurosciences [q-bio.NC]

I. Lauritzen, R. Pardossi-Piquard, C. Bauer, E. Brigham, J.-D. Abraham, et al.. 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. Journal of Neuroscience, 2012, 32 (46), pp.16243-16255. ⟨10.1523/JNEUROSCI.2775-12.2012⟩. ⟨hal-02361307⟩