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Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Steixner-Kumar AA, Subramanian S, Möbius W, Göbbels S, Saher G, Zampar S, Wirths O, Thalmann M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA. Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease. bioRxiv. August 2, 2021
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Technical University Munich
This fascinating paper by Depp et al. greatly advances our understanding of how oligodendrocytes contribute to AD, and shows that there are clearly far more cell types involved in AD than previously suspected.
Myelin undergoes substantial pathological alterations during normal aging. A further understanding of such age-related myelin and its associated cellular responses is essential, as aging is a major risk factor for the most prevalent neurodegenerative diseases such as AD.
In this interesting study, Depp et al. investigated whether myelin degeneration is associated with changes in Aβ deposition by combining mouse models of AD with models of genetically induced hypomyelination or dysmyelination. They observed that in models in which myelin is present but dysfunctional, amyloid deposition is strongly induced. Interestingly, in models in which compact myelin is lacking, less amyloid is deposited. Thus, the authors conclude that defective myelin is an upstream factor of amyloid plaque deposition.
The authors come up with two mechanisms for how myelin defects drive amyloidosis. The first is based on increased APP processing within dysfunctional axons. The second is on the altered microglial responses induced by dys- and demyelination. The authors propose that microglia, once engaged in the clearance of defective myelin, are distracted from amyloid plaques.
This is clearly an important paper as it links myelin dysfunction to amyloid deposition, and provides plausible mechanisms of how this might occur.
George Bartzokis was one of the first who postulated in a series of review papers that myelin breakdown could be connected to AD pathology. He proposed in his opinion papers that myelin-associated factors such as iron could be key in promoting toxicity and depositing amyloid. However, the fact that myelin is enriched in the white matter whereas amyloid plaque deposition occurs predominantly in the gray matter had always been an argument in contradiction to his model.
Yet, it is important to remember that myelin is not exclusive to the white matter. A substantial fraction of the axons within the gray matter is myelinated, and Depp et al. studied in particular the intracortical myelin in their paper. Their findings suggest that age-dependent loss of myelin integrity as it occurs in the gray and white matter under normal aging can be a risk factor for amyloid deposition.
Together with work from Bart de Strooper’ s lab (Chen et al., 2020) which identified myelin/oligodendrocyte gene responses around early amyloid plaques, the study by Depp et al. suggest that myelin dysfunction could be an early event in amyloid plaque deposition.
References:
Chen WT, Lu A, Craessaerts K, Pavie B, Sala Frigerio C, Corthout N, Qian X, Laláková J, Kühnemund M, Voytyuk I, Wolfs L, Mancuso R, Salta E, Balusu S, Snellinx A, Munck S, Jurek A, Fernandez Navarro J, Saido TC, Huitinga I, Lundeberg J, Fiers M, De Strooper B. Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease. Cell. 2020 Aug 20;182(4):976-991.e19. Epub 2020 Jul 22 PubMed.
View all comments by Mikael SimonsUniversity of Wisonsin
There have been several hints over the years that myelin and AD pathology are related. Braak and Braak made an early and key observation that brain regions that myelinate later in development are more vulnerable to development of AD pathology, and several neuroimaging studies have pointed toward white-matter degeneration and abnormalities across the continuum of AD. George Bartzokis was a strong proponent of the idea that myelin degeneration contributes to amyloid pathology and proposed a comprehensive model linking myelin to AD (among other disorders).
Our research group found that, among cognitively unimpaired middle-aged and older adults, cerebrospinal fluid levels of amyloid were related to myelin content measured with MRI. However, studying the link between myelin and AD pathology in humans is tricky. Neuroimaging studies of myelin are particularly challenging, given that myelin degeneration in aging and disease is also accompanied by regeneration (making it difficult to measure injury), and because it's challenging to establish the temporal ordering of events that occur in AD (myelin degeneration in relation to amyloid, tau, and neuronal injury/loss).
In this study, Depp et al. cleverly manipulated myelin in mice to better understand the direct links between myelin and amyloid. Based on a series of experiments with several mouse models ranging from those with myelin defects, to those where myelin was depleted, they found that amyloid deposition could either be enhanced or reduced. Perhaps one of the most intriguing observations to come from this series of experiments is in regard to the role of microglia, with the experiments suggesting that microglia busy themselves with myelin abnormalities to the point that they no longer engage in amyloid clearance. This is a completely new and fascinating piece of the myelin/AD puzzle.
Overall, the results greatly strengthen the myelin/AD link and will be highly encouraging to researchers focused on understanding white-matter abnormalities in AD.
View all comments by Barbara BendlinADvantage
This elegant report further supports the role of myelin breakdown in age-related neurodegeneration. We studied, for over three decades, the age-related changes that occur in the rhesus monkeys that lead to cognitive decline in otherwise healthy primates. The most striking changes seen at the biochemical, molecular biological, and ultrastructural levels were neuroinflammation in the white matter and the degeneration of myelin. Activated microglia and reactive astrocytes were seen only in the white matter of aged monkeys, but not in the gray matter (Sloane et al., 1999; Sloane et al., 2000). Activated microglia contained myelin debris, as seen by EM.
Only in old monkeys did we observe degraded myelin, including degraded CNPase, a major myelin protein (Sloane et al., 2003; Hinman et al., 2004; Hinman et al., 2008). Both calpain and the complement system were involved in myelin deterioration (Duce et al., 2006; Hinman and Abraham, 2007). Thus, just normal aging is enough to trigger myelin breakdown that, in a vicious cycle, is caused by, and further induces, microglia activation and phagocytosis. The hypothesis that microglia are ingesting myelin debris and not Aβ in the AD brain makes perfect sense.
References:
Sloane JA, Hollander W, Moss MB, Rosene DL, Abraham CR. Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging. 1999 Jul-Aug;20(4):395-405. PubMed.
Sloane JA, Hollander W, Rosene DL, Moss MB, Kemper T, Abraham CR. Astrocytic hypertrophy and altered GFAP degradation with age in subcortical white matter of the rhesus monkey. Brain Res. 2000 Apr 17;862(1-2):1-10. PubMed.
Sloane JA, Hinman JD, Lubonia M, Hollander W, Abraham CR. Age-dependent myelin degeneration and proteolysis of oligodendrocyte proteins is associated with the activation of calpain-1 in the rhesus monkey. J Neurochem. 2003 Jan;84(1):157-68. PubMed.
Hinman JD, Duce JA, Siman RA, Hollander W, Abraham CR. Activation of calpain-1 in myelin and microglia in the white matter of the aged rhesus monkey. J Neurochem. 2004 Apr;89(2):430-41. PubMed.
Duce JA, Hollander W, Jaffe R, Abraham CR. Activation of early components of complement targets myelin and oligodendrocytes in the aged rhesus monkey brain. Neurobiol Aging. 2006 Apr;27(4):633-44. Epub 2005 Jun 29 PubMed.
Hinman JD, Abraham CR. What's behind the decline? The role of white matter in brain aging. Neurochem Res. 2007 Dec;32(12):2023-31. Epub 2007 Apr 20 PubMed.
Hinman JD, Chen CD, Oh SY, Hollander W, Abraham CR. Age-dependent accumulation of ubiquitinated 2',3'-cyclic nucleotide 3'-phosphodiesterase in myelin lipid rafts. Glia. 2008 Jan 1;56(1):118-33. PubMed.
View all comments by Carmela AbrahamIt would be interesting to learn if these results hold in humans. As one example: Older adults with schizophrenia are more likely to be diagnosed with dementia (Stroup et al., 2021), experience accelerated brain aging (Oct. 2019 news), and to have had defects with myelin (Sui et al., 2021).
References:
Stroup TS, Olfson M, Huang C, Wall MM, Goldberg T, Devanand DP, Gerhard T. Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia. JAMA Psychiatry. 2021 Jun 1;78(6):632-641. PubMed.
Sui YV, Bertisch H, Lee HH, Storey P, Babb JS, Goff DC, Samsonov A, Lazar M. Quantitative Macromolecular Proton Fraction Mapping Reveals Altered Cortical Myelin Profile in Schizophrenia Spectrum Disorders. Cereb Cortex Commun. 2021;2(2):tgab015. Epub 2021 Feb 24 PubMed.
View all comments by Charles StromeyerMake a Comment
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