Abnormalities of the endosomal-lysosomal system occur in Alzheimer's disease (AD). Relatively little is known about multivesicular endosomes and their contributions to AD pathogenesis and maintenance of neuronal homeostasis, including exosome biogenesis and function. Our preliminary findings suggest that endosomal-lysosomal system dysfunction in AD, which prevents efficient transport and degradation of substrates, can be compensated for by enhanced secretion of exosomes containing neuroprotective factors along with toxic proteins.
In Aim 1 we will determine whether endosomal dysfunction (examined in Projects 1 and 4) and autophagic dysfunction (Project 2) affect exosome generation and secretion in mouse disease models.
In Aim 2, using in vivo and in vitro models, we will study the effects of enhancing or inhibiting lysosomal system function on exosome secretion and the reciprocal effects of enhancing or inhibiting exosome generation on AD-related lysosomal pathology. We demonstrated that cystatin C (CysC) can induce beneficial autophagic and lysosomal degradation and can also enhance exosomal secretion, resulting in neuroprotection. Both extracellular soluble human CysC and exogenous exosomes containing CysC protect cells from death. We propose that CysC can regulate whether proteins are directed to autophagic vesicles for lysosomal degradation or for release into the extracellular space via exosomes, and that both pathways potentially rescue deleterious effects of AD-related dysfunctions of the lysosomal system.
In Aim 3 we will test this hypothesis, demonstrating that reduced CysC levels, which are associated with AD, deprive cells of the protection provided by both soluble CysC and CysC-loaded exosomes. We will further determine whether therapeutic strategies that restore or enhance CysC activity will attenuate AD pathologies. Exosomal membrane-encased proteins are more stable than soluble proteins in the extracellular environment, offering long-lived and potentially spatially distant neuroprotective effects. Thus, exosomes released from cells in the central nervous system may have important protective functions, and CysC-loaded exosomes are a potential therapeutic strategy for the treatment of AD and other neurodegenerative disorders.
Mechanisms to eliminate toxic material are essential for cellular survival and fail In Alzheimer's disease. We will study how enhancing the secretion of exosomes, a recently identified vesicular pathway for releasing toxic material from the cell, might alleviate brain abnormalities and whether exosomes loaded with the protective protein cystatin C represent a novel therapeutic strategy for the treatment of neurodegenerative disorders.
|Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of vulnerable CA1 pyramidal neurons in young-Middle-Aged Ts65Dn mice. J Comp Neurol 523:61-74|
|Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). Brain Struct Funct 220:2983-96|
|Kelley, Christy M; Powers, Brian E; Velazquez, Ramon et al. (2014) Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. Brain Pathol 24:33-44|
|Counts, Scott E; Alldred, Melissa J; Che, Shaoli et al. (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172-9|
|Yan, Jian; Ginsberg, Stephen D; Powers, Brian et al. (2014) Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. FASEB J 28:4312-23|
|Xue, Xue; Wang, Li-Rong; Sato, Yutaka et al. (2014) Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer's disease. Nano Lett 14:5110-7|
|Kaur, Gurjinder; Sharma, Ajay; Xu, Wenjin et al. (2014) Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down's syndrome. J Neurosci 34:5099-106|
|Kelley, Christy M; Powers, Brian E; Velazquez, Ramon et al. (2014) Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice. J Comp Neurol 522:1390-410|
|Wesson, Daniel W; Morales-Corraliza, Jose; Mazzella, Matthew J et al. (2013) Chronic anti-murine Aýý immunization preserves odor guided behaviors in an Alzheimer's ýý-amyloidosis model. Behav Brain Res 237:96-102|
|Nixon, Ralph A (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983-97|
Showing the most recent 10 out of 105 publications