ABSRACT The metabolism of amyloid precursor protein (APP) and amyloid-? peptide (A?) are critical determinants of Alzheimer's disease (AD) pathogenesis. APP is a type-1 transmembrane protein which resides in the plasma membrane. A fraction of APP undergoes endocytosis and is trafficked to late endosomes, where proteolytic cleavage by ?- and ?-secretase results in the liberation of A? which is released into the extracellular space (interstitial fluid, ISF), even in normal individuals. Elevated levels of ISF A? may promote aggregation into soluble oligomers and insoluble amyloid plaques, and subsequent development of AD pathology. In addition to production, A? degradation and clearance significantly influences ISF A? levels and plaque pathogenesis. It has been postulated that age-related and disease-specific lysosomal dysfunction drives AD pathogenesis. While the specific underlying causes of lysosomal dysfunction continue to be unraveled, the resultant disease- promoting mechanisms may depend upon the cell type. For example in neurons, where A? is produced, physiologic lysosomal proteolysis may favor complete, non-amyloidogenic APP processing and/or A? degradation prior to release. In astrocytes, lysosomal activity may be important for catabolism of extracellular A? (and possibly amyloid fibrils) taken up intracellularly;while in microglia, it may promote clearance of the phagocytosed amyloid deposits. Understanding the role of cell-type specific lysosomal dysfunction in AD pathogenesis will be critical for identifying potential targets for intervention. Ubiquitously expressed Transcription Factor EB (TFEB), has been recently identified as a master regulator of lysosome biogenesis, endocytosis, and autophagy. While drugs are currently available (e.g., rapamycin) that stimulate autophagy, the TFEB-regulated transcriptional program coordinately increases flux through multiple lysosomal degradative pathways;and is sufficient to alleviate abnormal substrate accumulation and pathology in various lysosome storage diseases. Our preliminary data demonstrate that exogenous TFEB expression decreased A? production/release by N2a-APP695 cells (a neuroblastoma cell model of APP processing) compared with controls. In addition, TFEB expression in N2a cells resulted in increased uptake and accelerated degradation of exogenously applied A?. These data suggest that TFEB-induced lysosome biogenesis enhances APP and A? degradation through several cellular mechanisms. In this proposal, we hypothesize that enhancing lysosome biogenesis with exogenous expression of TFEB will suppress AD pathogenesis in a cell-type specific manner: in neurons, TFEB will facilitate complete proteolysis of APP and A? resulting in decreased A? generation and reduction in steady-state ISF A? levels;while in astrocytes, it will enhance A? uptake and degradation, resulting in reduced ISF A? half-life. Both mechanisms will attenuate amyloid plaque deposition. We will test this hypothesis in the following aims: 1. Determine the effect of TFEB-induced lysosomal biogenesis on APP processing and A? production in neurons. 2. Determine the effect of astrocytic expression of TFEB on A? and amyloid catabolism, and plaque growth.
Public Health and Clinical Relevance Alzheimer's disease (AD) is the leading cause of dementia throughout the world. With the aging population, the prevalence of AD is increasing rapidly. Understanding how the metabolism of A? and APP lead to the disease will be important for developing potential therapeutic targets. This R21 grant proposes to study the role of lysosomal degradation pathways in A? and APP metabolism and the development of AD pathology.
|Xiao, Qingli; Yan, Ping; Ma, Xiucui et al. (2015) Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing AÎ² Generation and Amyloid Plaque Pathogenesis. J Neurosci 35:12137-51|
|Yan, Ping; Zhu, Alec; Liao, Fan et al. (2015) Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy. Stroke 46:1633-40|
|Liao, Fan; Jiang, Hong; Srivatsan, Subhashini et al. (2015) Effects of CD2-associated protein deficiency on amyloid-Î² in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener 10:12|
|Xiao, Qingli; Yan, Ping; Ma, Xiucui et al. (2014) Enhancing astrocytic lysosome biogenesis facilitates AÎ² clearance and attenuates amyloid plaque pathogenesis. J Neurosci 34:9607-20|
|Sheline, Yvette I; West, Tim; Yarasheski, Kevin et al. (2014) An antidepressant decreases CSF AÎ² production in healthy individuals and in transgenic AD mice. Sci Transl Med 6:236re4|