A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons.
J Alzheimers Dis
; 83(2): 833-852, 2021.
Article
in En
| MEDLINE
| ID: mdl-34366358
ABSTRACT
BACKGROUND:
Processing of the amyloid-ß protein precursor (AßPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid ß-peptide (Aß42), which is a key player in Alzheimer's disease.OBJECTIVE:
Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aß42 and its immediate substrate AßPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy.METHODS:
Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses.RESULTS:
The first (ß-secretase) and second (γ-secretase) cleavages of AßPP were localized to functionally and distally distinct compartments. The ß-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aß42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aß42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AßPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aß42 were localized in different compartments.CONCLUSION:
These findings provide critical super-resolved insight into amyloidogenic AßPP processing in primary neurons.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Protein Precursor
/
Amyloid Precursor Protein Secretases
/
Alzheimer Disease
/
Hippocampus
/
Microscopy
/
Neurons
Limits:
Animals
/
Humans
Language:
En
Journal:
J Alzheimers Dis
Journal subject:
GERIATRIA
/
NEUROLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Suecia