Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia and neurodegeneration. Mutations in the Presenilin (PSEN) genes account for >80% of all causative mutations identified in familial AD, highlighting its importance in the pathogenesis of AD. Through the development and multidisciplinary analysis of a series of Psen mutant mice, we previously established that Presenilin (PS) is essential for learning and memory, synaptic function and neuronal survival. For example, presynaptic PS plays a selective role in neurotransmitter release and synaptic plasticity through the regulation of ryanodine receptors (RyRs) and RyR-mediated calcium release from the ER. Synaptic dysfunction has widely been considered to play a key role in AD pathogenesis, and the hippocampal network is particularly vulnerable in AD. However, published reports have largely focused on the hippocampal Schaffer collateral pathway, and rarely explored in the mossy fiber and the perforant path. Furthermore, inhibitory interneurons play an integral role in the regulation of neuronal networks, but it is entirely unknown whether PS plays a normal physiological role in interneurons. In this competing renewal application, we propose two Specific Aims to investigate the role of PS in the regulation of the hippocampal network and the pathogenic mechanism of familial AD.
In Aim 1, we will determine and compare the role of PS in the tri-synaptic loop of the hippocampus. Specifically, we will determine the consequences of PS inactivation in mossy fiber and perforant synapses, relative to Schaffer collateral synapses, using acute hippocampal slices. We will also investigate the role of PS in inhibitory interneurons through the generation and analysis of interneuron-specific conditional double knockout mice.
In Aim 2, we will investigate the role of PS in familial AD. Specifically, we will compare mouse neurons derived from knockin mice carrying the pathogenic PSEN1 L435F or C410Y mutation with human neurons derived from iPS cells carrying the same mutation, and will assess the effects of the mutation on ?-secretase activity, calcium regulation and synaptic function between the mouse and human neurons. The completion of the proposed study will provide mechanistic insight into PS function and dysfunction in excitatory and inhibitory neurons as well as its involvement in familial AD.

Public Health Relevance

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and mutations in the Presenilin genes are the most common cause of the inherited forms of the disease. The hippocampus is particularly vulnerable in AD, and synaptic dysfunction is widely considered as the earliest pathogenic event. In this application, we propose to study the normal function of Presenilins in the hippocampal network and how the mutations cause familial AD. Completion of our proposed study will provide insights into AD pathogenesis and may identify novel therapeutic targets for AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Mcgavern, Linda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
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
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
Kelleher 3rd, Raymond J; Shen, Jie (2017) Presenilin-1 mutations and Alzheimer's disease. Proc Natl Acad Sci U S A 114:629-631
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; S├╝dhof, 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

Showing the most recent 10 out of 32 publications