Cycle 3 project 8

Membrane trafficking in the maintenance of dendritic spine morphology – implications for Alzheimer’s Disease

 

PhD student: Vinod Udayar, India
Home Institute: Neuroscience Center Zürich; Principle Investigator: Lawrence Rajendran
Host Institutes:
Bordeaux Neurocampus; Principle Investigator: Valentin Nägerl
Amsterdam Neuroscience; Principle Investigator: Philip Scheltens

Executive Summary

The human brain is a network of billions of nerve cells that communicate through specialized connections called synapses. Changes in the strength of these synapses, termed synaptic plasticity, are essential for learning and memory. Synaptic dysfunction is the major cause of neurodegeneration and cognitive decline observed in age-related disorders such as Alzheimer’s disease (AD)

Alzheimer’s disease is characterized by the gradual decline in cognitive abilities paralleled by the accumulation of extracellular amyloid deposits primarily made of a peptide called amyloid β peptide (Aβ). This peptide either in its soluble, oligomeric form or in the classic plaque associated form is causatively linked to neurodegeneration. Recent data suggests that this peptide induces synaptic dysfunction by altering dendritic spine morphology. Our lab has been studying the cell biology of the amyloid β peptide production. We particularly focus on understanding the subcellular compartment where this peptide is produced and also systematically tease apart the membrane trafficking machinery involved. Having identified that early endosomes are the stations where Aβ peptides are produced we engineered a transition-state inhibitor of β-secretase with a lipid anchor so that this inhibitor is transported specifically to early endosomes and inhibit the peptide production. This approach has proven to be effective both in vitro and in mice models. Thus understanding the membrane trafficking pathways would enable a better comprehension of the disease as well as designing effective therapeutic strategies.

We have now carried out a focused membrane trafficking screen to identify all the trafficking pathways involved. Interestingly some of the pathways are also implicated in the maintenance of dendritic spine morphology suggesting a common node/pathway. While imaging studies have revolutionized our understanding of morpho-functional plasticity of dendritic spines, several questions still remain, among which a key one would be: Which trafficking pathway(s) provides the membrane to the formation and maintenance of dendritic spines? A combination of high-resolution live-cell microscopy and elegant molecular cell biology would clearly advance our current understanding of this basic process. In this proposal, we aim at screening for membrane trafficking pathways using lentivirus mediated transduction of regulators of trafficking combined with superresolution imaging of dendritic spines using Stimulation Emission Depletion Microscopy (STED). Results from this project will, for the first time, provide a comprehensive view on the role of all the membrane trafficking pathways involved in the maintenance of dendritic spine morphology. Needless to say this will have immediate implications for synaptic failure diseases such as Alzheimer’s disease.

 

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