Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, Borchelt DR.
Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits.
Acta Neuropathol Commun. 2015 Nov 14;3:72.
PubMed.
This is the first study showing that mouse Aβ forms amyloid plaques. It uses two completely different lines of mice. Both show amyloid plaques; one forms hardcore plaque, the other forms diffuse plaque. There is no obvious explanation for why these plaques have different morphology, but it is fascinating. The paper found the diffuse plaques only have Aβ42 and that Aβ42 is only SDS-soluble. Almost no SDS-insoluble fraction was detected.
It is also the first study to put together all the mouse cerebellum plaque information.
This paper by Xu et al. is another example that rodent Aβ not only can, but indeed does, aggregate, and does produce amyloid deposits in vivo. That the primary sequence of rodent Aβ is compatible with aggregation of the peptide into amyloid plaques similar to those seen in the Alzheimer's disease brain is an important result, and may help to focus attention on aspects of the disease that are independent of the unique properties of the human N-terminal region in Aβ.
We knew for a long time that murine neuronal lines, expressing endogenous Aβ, could be used to study the mechanisms of formation of Aβ oligomers, particularly those that form inside neurons. We began such studies more than 10 years ago when we observed that CAD cells—mouse neurons originating in the locus coeruleus (a region of the brain highly relevant to AD) (Braak and Del Tredici, 2011; Braak et al., 2011; Brettschneider et al., 2015; Muresan and Muresan, 2008)—are prone to accumulate oligomeric forms of Aβ (i.e., endogenous, mouse Aβ), both in the soma and at neurite terminals (Muresan and Muresan, 2012; Muresan et al., 2009; Muresan and Muresan, 2006). Not many supported our studies at that time. It was widely assumed that wild-type mice did not develop AD pathology because the primary sequence of rodent and human Aβ differ. Now, it seems clear that the mechanisms that lead to Aβ aggregation and plaque formation are not related—at least not entirely—to the particular amino acid sequence of the human, as opposed to rodent, Aβ.
Zoia Ladescu Muresan contributed to this comment.
References:
Braak H, Del Tredici K.
The pathological process underlying Alzheimer's disease in individuals under thirty.
Acta Neuropathol. 2011 Feb;121(2):171-81.
PubMed.
Braak H, Thal DR, Ghebremedhin E, Del Tredici K.
Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.
J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9.
PubMed.
Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ.
Spreading of pathology in neurodegenerative diseases: a focus on human studies.
Nat Rev Neurosci. 2015 Feb;16(2):109-20. Epub 2015 Jan 15
PubMed.
Muresan Z, Muresan V.
Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
Neurodegener Dis. 2008;5(3-4):250-3. Epub 2008 Mar 6
PubMed.
Muresan V, Muresan Z.
A persistent stress response to impeded axonal transport leads to accumulation of amyloid-β in the endoplasmic reticulum, and is a probable cause of sporadic Alzheimer's disease.
Neurodegener Dis. 2012;10(1-4):60-3.
PubMed.
Muresan V, Varvel NH, Lamb BT, Muresan Z.
The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites.
J Neurosci. 2009 Mar 18;29(11):3565-78.
PubMed.
Muresan Z, Muresan V.
Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
Mol Cell Biol. 2006 Jul;26(13):4982-97.
PubMed.
Comments
This is the first study showing that mouse Aβ forms amyloid plaques. It uses two completely different lines of mice. Both show amyloid plaques; one forms hardcore plaque, the other forms diffuse plaque. There is no obvious explanation for why these plaques have different morphology, but it is fascinating. The paper found the diffuse plaques only have Aβ42 and that Aβ42 is only SDS-soluble. Almost no SDS-insoluble fraction was detected.
It is also the first study to put together all the mouse cerebellum plaque information.
Rutgers - New Jersey Medical School
This paper by Xu et al. is another example that rodent Aβ not only can, but indeed does, aggregate, and does produce amyloid deposits in vivo. That the primary sequence of rodent Aβ is compatible with aggregation of the peptide into amyloid plaques similar to those seen in the Alzheimer's disease brain is an important result, and may help to focus attention on aspects of the disease that are independent of the unique properties of the human N-terminal region in Aβ.
We knew for a long time that murine neuronal lines, expressing endogenous Aβ, could be used to study the mechanisms of formation of Aβ oligomers, particularly those that form inside neurons. We began such studies more than 10 years ago when we observed that CAD cells—mouse neurons originating in the locus coeruleus (a region of the brain highly relevant to AD) (Braak and Del Tredici, 2011; Braak et al., 2011; Brettschneider et al., 2015; Muresan and Muresan, 2008)—are prone to accumulate oligomeric forms of Aβ (i.e., endogenous, mouse Aβ), both in the soma and at neurite terminals (Muresan and Muresan, 2012; Muresan et al., 2009; Muresan and Muresan, 2006). Not many supported our studies at that time. It was widely assumed that wild-type mice did not develop AD pathology because the primary sequence of rodent and human Aβ differ. Now, it seems clear that the mechanisms that lead to Aβ aggregation and plaque formation are not related—at least not entirely—to the particular amino acid sequence of the human, as opposed to rodent, Aβ.
Zoia Ladescu Muresan contributed to this comment.
References:
Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.
Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015 Feb;16(2):109-20. Epub 2015 Jan 15 PubMed.
Muresan Z, Muresan V. Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology. Neurodegener Dis. 2008;5(3-4):250-3. Epub 2008 Mar 6 PubMed.
Muresan V, Muresan Z. A persistent stress response to impeded axonal transport leads to accumulation of amyloid-β in the endoplasmic reticulum, and is a probable cause of sporadic Alzheimer's disease. Neurodegener Dis. 2012;10(1-4):60-3. PubMed.
Muresan V, Varvel NH, Lamb BT, Muresan Z. The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. PubMed.
Muresan Z, Muresan V. Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. PubMed.
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