Title | A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Yu, Y, Gao, Y, Winblad, B, Tjernberg, LO, Schedin-Weiss, S |
Journal | J Alzheimers Dis |
Volume | 83 |
Issue | 2 |
Pagination | 833-852 |
Date Published | 2021 |
ISSN | 1875-8908 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Amyloidogenic Proteins, Animals, Cells, Cultured, Hippocampus, Humans, Mice, Mice, Inbred C57BL, Microscopy, Neurons, Peptide Fragments, Protein Transport |
Abstract | BACKGROUND: Processing of the amyloid-β protein precursor (AβPP) 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 β-peptide (Aβ42), 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 Aβ42 and its immediate substrate AβPP 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 (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-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 Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. CONCLUSION: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons. |
DOI | 10.3233/JAD-215008 |
Alternate Journal | J Alzheimers Dis |
PubMed ID | 34366358 |
PubMed Central ID | PMC8543249 |