| First Author | Lauritzen I | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 46 | Pages | 16243-1655a |
| PubMed ID | 23152608 | Mgi Jnum | J:192455 |
| Mgi Id | MGI:5465211 | Doi | 10.1523/JNEUROSCI.2775-12.2012 |
| Citation | Lauritzen I, et al. (2012) The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not Abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci 32(46):16243-55a |
| abstractText | Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated beta-amyloid precursor protein (betaAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-beta peptides (Abeta) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Abeta 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 beta-secretase-derived betaAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of gamma-secretase. Notably, intracellular Abeta is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Abeta 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 betaAPP(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 gamma-secretase. Together, our work identifies C99 as the earliest betaAPP catabolite and main contributor to the intracellular betaAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model. |
