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Project Details
Description
Summary A pro-inflammatory signature accompanied by changes in cellular proteostasis are observed in
brain neurodegenerative conditions such as AD and to less extent in the aging brain. However, despite the
great advancement towards the understanding of the connection between inflammation, AD development and
aging-related pathologies, there are several important aspects, which are still very much under investigated.
For example albeit it is appreciate the existence of the lymphatic system, as a brain-to-periphery
communication conduit, it is still unknown the role played by the lymph in the inflammatory/degenerative
process occurring in the brain parenchyma and in transporting the brain molecular signature to the cervical
nodes for immune-surveillance. Another important aspect, yet to be investigated, are the very early changes in
endosomal proteostasis and the proteome post-translational modifications, occurring before bona fide AD and
aging degenerative changes are observed. Finally, despite the fact that active and passive immunotherapy has
been proposed for AD the role of MHCII-restricted immune response to naturally processed TAU, Aβ and other
brain self-antigens is still unknown. As such the trust of this application is to: (i) explore the role played by the
lymphatic circulation in transporting the inflammatory/degenerative molecular signature of the brain
parenchyma to the draining cervical node (with P1 and Core B) (ii) map the very early changes in the brain
proteome, PTM- modifications, endo-lysosomal proteostasis and autophagic machinery (with P1 and Core C)
(iii) analyze changes in the MHC II-restricted immune-peptidome, and related T cell responses, during aging
and the different phases of AD progression (with P3 and Core B). By using state-of the art quantitative
proteomic, associated with a cell biology approach, we will map proteins PTMs at different stages of the aging
process and AD development as well as their effect on endo-lysosomal proteostasis and the autophagic
machinery. Additionally we will investigate the lymph inflammatory/degenerative signature in young and old
mice, as well as, AD mice at different stage of disease. Finally, the MHC II-immunopeptidome, eluted from
dendritic cells in the cervical node, will be analyzed by MS/MS to map peptides derived from brain-relevant
proteins in aging and at different stages of AD. Tetramer staining, using relevant MHC-II-peptides, will be
employed to analyze T cell recognition and address the overall immune responses to brain antigens.
Altogether results from this project will provide a progressive snap shot of how the cellular proteome is
modified during the early-to-late stages of AD or aging development, how the autophagic machinery is involved
in disposing the modified proteome, how these early changes progressively develop into complex aggregates
and how the endo-lysosomal system is involved in restoring proteostasis. Additionally, how the lymphatic
system function as a conduit to transport the inflammatory/degenerative phenotype associated with AD
development to the immune system and conversely how immune cells respond to proteomic changes in aging
and during AD progression.
Status | Finished |
---|---|
Effective start/end date | 4/1/20 → 3/31/24 |
Funding
- National Institute on Aging: $390,566.00
- National Institute on Aging: $391,440.00
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Projects
- 1 Finished
-
Autophagy in aging: testing geroscience in Alzheimer's disease
Cuervo, A. M., Bravo Cordero, J. J., Gavathiotis, E., Macian-Juan, F., Santambrogio, L. & Singh, R.
2/15/09 → 3/31/24
Project: Research project