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 hippocampusspecific 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.

Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer’s disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery of the active spliced transcription factor X-Box binding protein 1s (XBP1s) in the hippocampus rescued spine density, synaptic plasticity and memory function in a mouse model of AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), a protein that controls synaptic plasticity. In addition, we found reduced levels of Kal7 in primary neurons exposed to Aβ oligomers, transgenic mouse models and human AD brains. Short hairpin RNA-mediated knockdown of Kal7 altered synaptic plasticity and memory formation in naive mice. Further, reduction of endogenous Kal7 compromised the beneficial effects of XBP1s in Alzheimer’s model. Hence, our findings reveal that XBP1s is neuroprotective through a mechanism that engages Kal7 pathway with therapeutic implications in AD pathology.