Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

Savas, Jeffrey N.; Wang, Yi Zhi; DeNardo, Laura A; Martínez‐Bartolomé, Salvador; McClatchy, Daniel B.; Hark, Timothy J.; Shanks, Natalie F.; Cozzolino, Kira A.; Lavallée‐Adam, Mathieu; Smukowski, Samuel N.; Park, Sung Kyu; Kelly, Jeffery W.; Koo, Edward H.; Nakagawa, Terunaga; Masliah, Eliezer; Ghosh, Anirvan; Yates, John R.

doi:10.1016/j.celrep.2017.11.009

Cited by 58 publications

(38 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the effects of HIV-1, we explored the impact of Aβ on the HBMEC-EV proteome in the context of HIV-1. It was reported that increased brain Aβ induced profound proteome remodeling in multiple cell types, altering brain molecular pathways in an Alzheimer's disease (AD) mouse model [24]. Another brain proteomic study using a different AD mouse model with amyloid and neurofibrillary tangle pathologies indicated age-dependent immune responses and synaptic dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles

András

Sewell

Toborek

2020

IJMS

View full text Add to dashboard Cite

Amyloid beta (Aβ) depositions are more abundant in HIV-infected brains. The blood-brain barrier, with its backbone created by endothelial cells, is assumed to be a core player in Aβ homeostasis and may contribute to Aβ accumulation in the brain. Exposure to HIV increases shedding of extracellular vesicles (EVs) from human brain endothelial cells and alters EV-Aβ levels. EVs carrying various cargo molecules, including a complex set of proteins, can profoundly affect the biology of surrounding neurovascular unit cells. In the current study, we sought to examine how exposure to HIV, alone or together with Aβ, affects the surface and total proteomic landscape of brain endothelial EVs. By using this unbiased approach, we gained an unprecedented, high-resolution insight into these changes. Our data suggest that HIV and Aβ profoundly remodel the proteome of brain endothelial EVs, altering the pathway networks and functional interactions among proteins. These events may contribute to the EV-mediated amyloid pathology in the HIV-infected brain and may be relevant to HIV-1-associated neurocognitive disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles

András

Sewell

Toborek

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…In fact, this has been shown to be the case, as treatment of cultures with anti-C1q antibody inhibited microgliamediated synaptic elimination. In contrast, other proteomics studies failed to identify the enrichment of complement components in the hAPP mouse model and in AD patient post-mortem brain samples [200,201]. These contradictory data indicate that more studies should be conducted to fully clarify the role of the complement cascade in AD, aiming at distinguishing whether the progressive C1q accumulation at synapses, found by Dejanovic et al [199], is a sole consequence of the disorder or is also affected by the aging process.…”

Section: Overheating the Developmental Engine In Ad: When Complement-mentioning

confidence: 97%

Synaptic Elimination in Neurological Disorders

Cardozo

Lima

Maciel

et al. 2019

View full text Add to dashboard Cite

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.

show abstract

“…There is also increased appreciation that better mouse models are needed to identify targets for therapeutic intervention in neurodegenerative diseases, including AD (Drummond and Wisniewski, 2017). The comprehensive proteome dynamics provided insights that enable the direct comparison of multiple different mouse models (Savas et al, 2017). Comparing the over-expressing hAPP transgenic model (TgCRND8) at early and late stages of the disease indicated large yet discordant effects on protein turnover.…”

Section: Discussionmentioning

confidence: 99%

Multidimensional dynamics of the proteome in the neurodegenerative and ageing mammalian brain

Andrews

Almeida-Souza

Skehel

et al. 2018

Preprint

View full text Add to dashboard Cite

The amount of any given protein in the brain is determined by the rates of its synthesis and destruction, which are regulated by different cellular mechanisms.Here, we combine metabolic labelling in live mice with global proteomic profiling to simultaneously quantify both the flux and amount of proteins in mouse models of neurodegeneration. In multiple models, protein turnover increases were associated with increasing pathology. This method distinguishes changes in protein expression mediated by synthesis from those mediated by degradation. In the App NL-F knockin mouse model of Alzheimer's disease increased turnover resulted from imbalances in both synthesis and degradation, converging on proteins associated with synaptic vesicle recycling (Dnm1, Cltc, Rims1) and mitochondria (Fis1, Ndufv1). In contrast to disease models, ageing in wildtype mice caused a widespread decrease in protein recycling associated with a 2 decrease in autophagic flux. This simple multidimensional approach enables the comprehensive mapping of proteome dynamics and identifies affected proteins in mouse models of disease and other live animal test settings.

show abstract

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

Cited by 58 publications

References 77 publications

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles

Synaptic Elimination in Neurological Disorders

Multidimensional dynamics of the proteome in the neurodegenerative and ageing mammalian brain

Contact Info

Product

Resources

About