Very interesting paper. This paper describes for the first time that Amyloid Precursor Protein is organized into regulatory nanodomains and APPs are reversibly immobilized on membrane. The article uses multiple paradigms of the state-of-the-art super-resolution microscopy techniques and analysis to decipher several novel observations which might be crucial for the AD field.
The paper deals with the nano organization of APP at excitatory synapses alongside real-time trafficking of APP molecules in live cells with interesting observations of differences in mobility patterns for variants of APP implicated in AD. This investigation might open new avenues for more functional studies related to amyloidogenic processing of APP, and how local changes might influence product formation.
The paper investigates a very interesting and currently underrepresented aspect of APP biology and processing. It investigates with elegant, super-resolution microscopy the localization of soluble and membrane-bound APP. The authors show that the availability and composition of APP as well as secretase complexes at the synapses are central for cleavage and availability. Most importantly, they show that mutations in APP affect its ability for lateral diffusion. This directly affects the availability of APP molecules per unit time per unit area. This is an exciting piece of work looking closely into these aspects, which are highly relevant for understanding APP biology in normal and diseased conditions.
This study with super-resolution microscopy presents a nanoscale topography of amyloid precursor protein molecules. Additionally, the authors describe the kinetics of APP molecules with data showing they are immobilized inside a cluster of APP molecules referred as "Nanodomain." The authors discuss what influence this could have on the cleavage of APP. This is especially important in the context of the differences in the kinetics of different species of APP employed in this study.
This is a fantastic study looking at the nanoscale organization and dynamics of APP at synapses using state-of-the-art super-resolution microscopy. Kedia et al. show that APP is organized in nanodomains and that individual APP molecules can dynamically move in and out these nanodomains. Highlighting their potential relevance to disease, the authors showed that APP mutants associated with familial forms of Alzheimer’s disease (APPswe) displayed aberrant dynamics and organization. Although at the very early stages, this study sets the stage for exciting further experiments elucidating the role of APP nanoscale organization and dynamics in the formation of the Aβ peptides and ultimately, its contribution to Alzheimer’s disease pathology. I can’t wait for the follow-up!
The investigations by Kedia et al. demonstrate the mapping of nanoscale topography of amyloid precursor protein. This is useful as it unpins the variations in the nanoorganization in different functional zones of the synapse in hippocampal neurons. Additionally, the authors incorporate these details in silico into a realistic model to visualize the heterogeneity in the distribution. Moreover, with the aid of live-cell super-resolution imaging, Kedia et al. show the kinetics pattern of APP molecules and its aberrant mobility pattern in a variant implicated in AD. Altogether, this study offers interesting insight which is important for the field, and in future should be extended to functional studies directed at understanding the variability in Aβ generation.
— P. Ramakrishna, P.R. Netrakanti, M. Jose, J.B. Sibarita, S. Nadkarni, and D. Nair are co-authors of this comment.
Comments
Very interesting paper. This paper describes for the first time that Amyloid Precursor Protein is organized into regulatory nanodomains and APPs are reversibly immobilized on membrane. The article uses multiple paradigms of the state-of-the-art super-resolution microscopy techniques and analysis to decipher several novel observations which might be crucial for the AD field.
The paper deals with the nano organization of APP at excitatory synapses alongside real-time trafficking of APP molecules in live cells with interesting observations of differences in mobility patterns for variants of APP implicated in AD. This investigation might open new avenues for more functional studies related to amyloidogenic processing of APP, and how local changes might influence product formation.
University Copenhagen
The paper investigates a very interesting and currently underrepresented aspect of APP biology and processing. It investigates with elegant, super-resolution microscopy the localization of soluble and membrane-bound APP. The authors show that the availability and composition of APP as well as secretase complexes at the synapses are central for cleavage and availability. Most importantly, they show that mutations in APP affect its ability for lateral diffusion. This directly affects the availability of APP molecules per unit time per unit area. This is an exciting piece of work looking closely into these aspects, which are highly relevant for understanding APP biology in normal and diseased conditions.
Institute of Genomics and Integrative Biology
This study with super-resolution microscopy presents a nanoscale topography of amyloid precursor protein molecules. Additionally, the authors describe the kinetics of APP molecules with data showing they are immobilized inside a cluster of APP molecules referred as "Nanodomain." The authors discuss what influence this could have on the cleavage of APP. This is especially important in the context of the differences in the kinetics of different species of APP employed in this study.
The University of Queensland
This is a fantastic study looking at the nanoscale organization and dynamics of APP at synapses using state-of-the-art super-resolution microscopy. Kedia et al. show that APP is organized in nanodomains and that individual APP molecules can dynamically move in and out these nanodomains. Highlighting their potential relevance to disease, the authors showed that APP mutants associated with familial forms of Alzheimer’s disease (APPswe) displayed aberrant dynamics and organization. Although at the very early stages, this study sets the stage for exciting further experiments elucidating the role of APP nanoscale organization and dynamics in the formation of the Aβ peptides and ultimately, its contribution to Alzheimer’s disease pathology. I can’t wait for the follow-up!
Sri Venkateswara College/ University of Delhi
The investigations by Kedia et al. demonstrate the mapping of nanoscale topography of amyloid precursor protein. This is useful as it unpins the variations in the nanoorganization in different functional zones of the synapse in hippocampal neurons. Additionally, the authors incorporate these details in silico into a realistic model to visualize the heterogeneity in the distribution. Moreover, with the aid of live-cell super-resolution imaging, Kedia et al. show the kinetics pattern of APP molecules and its aberrant mobility pattern in a variant implicated in AD. Altogether, this study offers interesting insight which is important for the field, and in future should be extended to functional studies directed at understanding the variability in Aβ generation.
— P. Ramakrishna, P.R. Netrakanti, M. Jose, J.B. Sibarita, S. Nadkarni, and D. Nair are co-authors of this comment.
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