The goal of the proposed project is to define the function of presenilin-1 (PS I) in the adult brain, including its role in the processing of the amyloid precursor protein (APP), Notch signalling, and synaptic function. Our previous studies of PS1-/-mice revealed a critical role for PS1 in neurogenesis, neuronal migration and Notch signalling during neural development. The perinatal lethality of PS1-/- mice precludes the analysis of PS1 function in the adult brain. We therefore developed a viable conditional PS1 knockout (cKO) mouse using the Cre/loxP recombination system, in which PS1 function is selectively inactivated in neurons of the postnatal forebrain. Here we propose to use the cKO mouse to investigate the role of PS1 in APP processing, generation of b-amyloid peptides and amyloid plaque formation in the adult cerebral cortex. We will also investigate whether disruption of PS 1 function in the adult brain leads to a reduction in Notch signalling as it does in the embryonic brain. Lastly, we will address whether PS1 is required for neuronal survival, synaptic transmission and plasticity, as well as learning and memory. The significance of the proposed study is that it will elucidate the normal physiological role of PS1 in the adult brain and test the feasibility and suitability of targeting PS1 for anti-amyloidogenic therapy in Alzheimer's disease.
| Dhaliwal, Jagroop; Kannangara, Timal S; Vaculik, Michael et al. (2018) Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2. Sci Rep 8:17931 |
| Kelleher 3rd, Raymond J; Shen, Jie (2017) Presenilin-1 mutations and Alzheimer's disease. Proc Natl Acad Sci U S A 114:629-631 |
| Kang, Jongkyun; Shin, Sarah; Perrimon, Norbert et al. (2017) An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain. Genetics 206:1479-1493 |
| Lee, Sang Hun; Lutz, David; Mossalam, Mohanad et al. (2017) Presenilins regulate synaptic plasticity and mitochondrial calcium homeostasis in the hippocampal mossy fiber pathway. Mol Neurodegener 12:48 |
| Watanabe, Hirotaka; Shen, Jie (2017) Dominant negative mechanism of Presenilin-1 mutations in FAD. Proc Natl Acad Sci U S A 114:12635-12637 |
| Xia, Dan; Kelleher 3rd, Raymond J; Shen, Jie (2016) Loss of A?43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain. Neuron 90:417-22 |
| Xia, Dan; Watanabe, Hirotaka; Wu, Bei et al. (2015) Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron 85:967-81 |
| Shen, Jie (2014) Function and dysfunction of presenilin. Neurodegener Dis 13:61-3 |
| Lee, Sang Hun; Sharma, Manu; Südhof, Thomas C et al. (2014) Synaptic function of nicastrin in hippocampal neurons. Proc Natl Acad Sci U S A 111:8973-8 |
| Watanabe, Hirotaka; Iqbal, Minah; Zheng, Jin et al. (2014) Partial loss of presenilin impairs age-dependent neuronal survival in the cerebral cortex. J Neurosci 34:15912-22 |
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