Kobro-Flatmoen A, Nagelhus A, Witter MP.
Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer's disease.
Neurobiol Dis. 2016 Sep;93:172-83. Epub 2016 May 16
PubMed.
Menno Witter is a leading expert on the anatomical organization of the hippocampal formation, i.e., the entorhinal cortex plus hippocampus proper. This latest manuscript, typical of the Witter lab in its elegance and rigor, informs on and resonates with a number of critical themes that relate to the location of Aβ:
1. Whether inside or outside of neurons. As pioneered by the Gouras lab, and as further validated by work by LaFerla and others in animal models, the Witter paper supports the emerging idea that Aβ begins to accumulate inside neurons, before being secreted by neurons into the extracellular space.
2. Where in neurons. It is now understood that Aβ is most likely to be produced inside endosomes. In fact, work by Gouras, Nixon, and others have shown that intracellular Aβ accumulates in the endosomal system. Mechanistically, this suggests that defects in endosomal trafficking can lead to accelerated Aβ production, as we have shown for retromer (a master conductor of endosomal trafficking), but also by other defects in endosomal trafficking.
3. Where in the entorhinal cortex. The entorhinal cortex is not a homogenous structure, but is made up of functionally and molecularly distinct neurons arranged along its three-dimensional organization. Witter’s recent work supports the idea that it is EC neurons closest to the rhinal fissure that accumulate intracellular Aβ. This anatomically overlaps with where pre-existing tau alterations begin. In our recent work (Khan et al., 2013), we used fMRI to show that it is EC neurons closest to the rhinal fissure that are particularly vulnerable to a combination of APP/tau expression.
Together, these series of conclusions can explain why the EC is differentially vulnerable to AD (i.e., because it is “tagged” by pre-existing tau alterations) and how this might happen (i.e., endosomal trafficking defects). They also suggest that intracellular Aβ might be the better target for therapeutic interventions during the earliest stages of AD.
References:
Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux R, Duff KE, Small SA.
Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
Nat Neurosci. 2014 Feb;17(2):304-11. Epub 2013 Dec 22
PubMed.
Comments
Columbia University
“Where, oh where, is Aβ?”
Menno Witter is a leading expert on the anatomical organization of the hippocampal formation, i.e., the entorhinal cortex plus hippocampus proper. This latest manuscript, typical of the Witter lab in its elegance and rigor, informs on and resonates with a number of critical themes that relate to the location of Aβ:
1. Whether inside or outside of neurons. As pioneered by the Gouras lab, and as further validated by work by LaFerla and others in animal models, the Witter paper supports the emerging idea that Aβ begins to accumulate inside neurons, before being secreted by neurons into the extracellular space.
2. Where in neurons. It is now understood that Aβ is most likely to be produced inside endosomes. In fact, work by Gouras, Nixon, and others have shown that intracellular Aβ accumulates in the endosomal system. Mechanistically, this suggests that defects in endosomal trafficking can lead to accelerated Aβ production, as we have shown for retromer (a master conductor of endosomal trafficking), but also by other defects in endosomal trafficking.
3. Where in the entorhinal cortex. The entorhinal cortex is not a homogenous structure, but is made up of functionally and molecularly distinct neurons arranged along its three-dimensional organization. Witter’s recent work supports the idea that it is EC neurons closest to the rhinal fissure that accumulate intracellular Aβ. This anatomically overlaps with where pre-existing tau alterations begin. In our recent work (Khan et al., 2013), we used fMRI to show that it is EC neurons closest to the rhinal fissure that are particularly vulnerable to a combination of APP/tau expression.
Together, these series of conclusions can explain why the EC is differentially vulnerable to AD (i.e., because it is “tagged” by pre-existing tau alterations) and how this might happen (i.e., endosomal trafficking defects). They also suggest that intracellular Aβ might be the better target for therapeutic interventions during the earliest stages of AD.
References:
Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux R, Duff KE, Small SA. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci. 2014 Feb;17(2):304-11. Epub 2013 Dec 22 PubMed.
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