Presenilin-1 Mutation Sensitizes Oligodendrocytes to Glutamate and Amyloid Toxicities, and Exacerbates White Matter Damage and Memory Impairment in Mice

Pak, Kirk J.; Chan, Sic L.; Mattson, Mark P.

doi:10.1385/nmm:3:1:53

Cited by 66 publications

(52 citation statements)

References 44 publications

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“…We hypothesized that myelin breakdown in vulnerable late-myelinating regions ( Figure 1B, D) releases oligodendrocyte-and myelin-associated iron [19,21,28,38,39], thus promoting Aβ oligomerization, its associated toxicity, and deposition of oligomerized Aβ and iron in neuritic plaques [7,28,[40][41][42][43] (Figure 1A, C). This hypothesis has been supported in transgenic mouse models that demonstrated increased vulnerability of oligodendrocytes to toxicity [44], agerelated white matter volume reductions [45], and age-related iron deposition in amyloid plaques [42]. Human studies have likewise confirmed age-related myelin breakdown that is exacerbated in healthy APOE e4 carriers and AD subjects [7,43] and age-related increases in brain iron [21] that are exacerbated in AD subjects [28].…”

Section: Methods Results and Discussionmentioning

confidence: 82%

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Bartzokis

Mintz

2007

Alzheimer's & Dementia

136

138

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We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte-and myelin-associated iron that promotes amyloid beta (Aβ) oligomerization, its associated toxicity, and the deposition of oligomerized Aβ and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of Aβ deposits in humans. The data show that in AD, radiolabeled ligands detect Aβ deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind Aβ in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

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Section: Methods Results and Discussionmentioning

confidence: 82%

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Bartzokis

Mintz

2007

Alzheimer's & Dementia

136

138

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“…The coexpression of PSEN1 with known myelin-associated genes in both studies, and its high connectivity in the AD study, suggests that PSEN1 may play a role in oligodendrocyte dysfunction or demyelination in AD. Pak et al (2003) found that oligodendrocytes in PSEN1 mutant knock-in mice were more prone to damage by demyelinating agents and death by glutamate and ␤-amyloid toxicity. These results fit the hypothesis that AD progression follows a trajectory opposite in time to cortical myelination (Braak and Braak, 1996), because the later-made oligodendrocytes progressively myelinate a greater number of axonal segments, making them more vulnerable to AD risk factors such as head injury and high cholesterol (Bartzokis, 2004).…”

Section: Discussionmentioning

confidence: 99%

A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging

Miller¹,

Oldham²,

Geschwind³

2008

J. Neurosci.

356

307

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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting millions of elderly individuals worldwide. Advances in the genetics of AD have led to new levels of understanding and treatment opportunities. Here, we used a systems biology approach based on weighted gene coexpression network analysis to determine transcriptional networks in AD. This method permits a higher order depiction of gene expression relationships and identifies modules of coexpressed genes that are functionally related, rather than producing massive gene lists. Using this framework, we characterized the transcriptional network in AD, identifying 12 distinct modules related to synaptic and metabolic processes, immune response, and white matter, nine of which were related to disease progression. We further examined the association of gene expression changes with progression of AD and normal aging, and were able to compare functional modules of genes defined in both conditions. Two biologically relevant modules were conserved between AD and aging, one related to mitochondrial processes such as energy metabolism, and the other related to synaptic plasticity. We also identified several genes that were central, or hub, genes in both aging and AD, including the highly abundant signaling molecule 14.3.3 (YWHAZ), whose role in AD and aging is uncharacterized. Finally, we found that presenilin 1 (PSEN1) is highly coexpressed with canonical myelin proteins, suggesting a role for PSEN1 in aspects of glial-neuronal interactions related to neurodegenerative processes.

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“…38,39 This familial AD mutation has been shown to hypersensitize oligodendrocytes to various insults associated with AD, including A␤ peptides. 40 Hence, it is possible that the A␤-induced changes in oligodendrocyte marker expression and myelin structure are at least partially mediated through oligodendrocyte-expressed PS1 M146V . Isolation of each potential genetic player in single and double-transgenic AD mice, as well as generation of conditional transgenics with oligodendrocyte-specific expression profiles, will help to differentiate "oligocentric" mechanisms from pathogenic signals indirectly derived from other A␤-assaulted cell types.…”

Section: Discussionmentioning

confidence: 99%

Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target

Desai

Mastrangelo

Ryan

et al. 2010

The American Journal of Pathology

182

173

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The detection of myelin disruptions in Alzheimer's disease (AD)-affected brain raises the possibility that oligodendrocytes undergo pathophysiological assault over the protracted course of this neurodegenerative disease. Oligodendrocyte compromise arising from direct toxic effects imparted by pathological amyloid-␤ peptides and/or through signals derived from degenerating neurons could play an important role in the disease process. We previously demonstrated that 3؋Tg-AD mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant alterations in overall myelination patterns and oligodendrocyte status at time points preceding the appearance of amyloid and tau pathology. Herein, we demonstrate that A␤ 1-42 leads to increased caspase-3 expression and apoptotic cell death of both nondifferentiated and differentiated mouse oligodendrocyte precursor (mOP) cells in vitro. Through use of a recombinant adeno-associated virus serotype-2 (rAAV2) vector expressing an A␤ 1-42 -specific intracellular antibody (intrabody), oligodendrocyte and myelin marker expression, as well as myelin integrity, were restored in the vector-infused brain regions of 3؋Tg-AD mice. Overall, this work provides further insights into the impact of A␤ 1-42 -mediated toxicity on the temporal and spatial progression of subtle myelin disruption during the early presymptomatic stages of AD and may help to validate new therapeutic options designed to avert these early impairments.

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Presenilin-1 Mutation Sensitizes Oligodendrocytes to Glutamate and Amyloid Toxicities, and Exacerbates White Matter Damage and Memory Impairment in Mice

Cited by 66 publications

References 44 publications

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Human brain myelination and amyloid beta deposition in Alzheimer's disease

A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging

Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target

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