The role of impaired SV machinery proteostasis in AD pathogenesis

Project: Research project

Description

AD is characterized histologically by an accumulation of misfolded amyloid- (A) peptides in extracellular amyloid plaques and an intracellular accumulation of hyper-phosphorylated tau protein in neurofibrillary tangles (NFTs), and clinically by a decline in memory function. Altered synapses lead to changes in the activity of neuronal circuits, which ultimately drive impaired cognition in AD. Understanding the underlying mechanisms that cause alterations in synaptic dysfunction in AD will represent a significant advancement toward the identification of new targets for effective drug therapy.
This proposed research builds on our recent global analysis of protein degradation dynamics in the brains of APP knock-in (APPKI) mice. Out of the thousands of proteins measured, we found degradation of the synaptic vesicle (SV) release and recycling machinery represented the earliest and most impaired class of proteins placing the presynaptic terminal as a key site in the early stages of disease. In this research, we will investigate if impaired trafficking, or altered protein-protein interactions, are responsible for hampering the SV machinery’s degradation with a combination of biochemistry and microscopy-based approaches. We will also investigate if SV cycling is altered in the context of A and or tau pathology. The proposed research will advance our understanding of the presynaptic protein networks that drive a key early pathological AD mechanism. Future therapeutic targeting of these identified protein networks may provide new and effective strategies to delay the onset of impaired synaptic transmission and associated AD cognitive impairment.
StatusActive
Effective start/end date1/1/1912/31/19

Funding

  • Alzheimer's Disease Research Foundation (AGMT 1/16/19)

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Synaptic Vesicles
Proteins
Research
tau Proteins
Neurofibrillary Tangles
Amyloid Plaques
Presynaptic Terminals
Recycling
Protein Transport
Amyloid
Synaptic Transmission
Biochemistry
Synapses
Cognition
Proteolysis
Microscopy
Pathology
Drug Therapy
Peptides
Brain