Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways

Greenberg, Steven M.; Bacskai, Brian J.; Hernández-Guillamón, Mar; Pruzin, Jeremy J.; Sperling, Reisa A.; Veluw, Susanne J. van

doi:10.1038/s41582-019-0281-2

Cited by 450 publications

(461 citation statements)

References 225 publications

(213 reference statements)

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“…CAA and vascular dysfunction was previously identified in WSB. APP/PS1 mice 6 and CAA is thought to be independent of neuroinflammation in human AD patients 42 . Recent work used the CSF1R inhibitor PLX5622 to deplete microglia in 5XFAD resulting in almost completely loss of amyloid in the parenchyma, and significant CAA and vascular leakage 43 .…”

Section: Discussionmentioning

confidence: 99%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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Microglia are now considered drivers of Alzheimer's disease (AD) pathology. However, single-cell RNA-sequencing (scRNA-seq) of microglia in mice, a key preclinical model organsim, have shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains WSB/EiJ, CAST/EiJ and PWK/PhJ carrying APP/PS1 was performed and demonstrated that genetic diversity significantly altered features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. There was significant variation in abundance of microglial subpopulations, including numbers of disease-associated microglia and interferon-responding microglia across the strains.Further, for each subpopulation, significant gene expression differences were observed between strains, and relative to B6 that included nineteen genes previously associated with human AD including Apoe, Trem2, Bin1 and Sorl1. This resource will be critical in the development of appropriately targeted therapeutics for AD and a range of other neurological diseases. 30 Introduction 31Alzheimer's disease (AD) is defined by the neuropathological accumulation of beta 32 amyloid plaques, neurofibrillary tangles of tau and widespread neuronal loss. AD is the 33 most common cause of adult dementia and is characterized by a wide range of 34 cognitive and behavioral deficits that severely impact quality of life and the ability to self-35 care. Recent work has re-focused the field towards the contribution of brain glial cells to 36 the initiation and spread of these disease-specific pathologies, and specifically on the 37 role of microglia as potentially a causative cell type in driving disease development and 38 progression. Human genome-wide association studies (GWAS) have identified more 39 than 25 variants near genes uniquely expressed in microglia that are predicted to 40 increase susceptibility for AD. In light of this complexity, the mouse represents a critical 41 model system to dissect the role of microglia and other glia in AD. 42 43There has been large debate regarding the alignment of mouse microglia to human 44 microglia in terms of identity, diversity and function. With the more widespread use of 45 single-cell sequencing technology, a number of groups have suggested that the species 46 difference is too great for conclusions drawn from mouse models to inform our 47 understanding of human microglia1,2. Central to this argument is the discovery and 48 description of a specific class of microglia in the mouse, disease-associated microglia 49 (DAM)3. Based upon the current data it is unclear whether the presence or absence of 50 DAM in human AD patients is the result of differences in tissue collection, extraction of 51 cells, genetic diversity of patients, sub-type of AD presented in donors or even the 52 relevant disease1,4. Recent work has demonstrated that single-nucleus RNA 53 sequencing of stored human tissue fails to detect differences in microglia activation 54 between AD and contro...

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Section: Discussionmentioning

confidence: 99%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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“…In AD, beta-amyloid deposits accumulate in the brain ISS [111][112][113], which increases the volume and tortuosity of ISS. It is believed that blockage of brain ISF drainage accelerates the abnormal deposition of betaamyloid in AD, which contributes to both cerebral amyloid angiopathy and neurodegeneration [23,114,115]. Changes in the ISS have also been reported in other diseases, such as Parkinson's disease [116], multiple sclerosis [117,118], and epilepsy [17,119].…”

Section: Status Of Iss In Neurological Disordersmentioning

confidence: 99%

The Interstitial System of the Brain in Health and Disease

Shetty

Zanirati

2020

Aging and disease

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The brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. Recently, with a newly developed in vivo measuring technique, a series of discoveries have been made in the brain ISS and the drainage of ISF. The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer's disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussed Key words: beta-amyloid, cerebrospinal fluid, extracellular matrix, extracellular vesicles, glymphatic system, interstitial fluid, phosphorylated tau contiguous glia, or the adjoining neurons and glia is also known as the extracellular space (ECS) [1-3].

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“…For several years, AD has been clinically characterized by progressive dementia with aberrant pathological deposits of intracellular NFTs and aggregation of extracellular Aβ peptides. Recent etiological studies of AD have focused on the vascular factors which participate in neuronal degeneration (Greenberg et al, 2020). In particular, oxidized low-density lipoprotein (oxLDL) has been demonstrated to contribute to AD pathology by regulating Aβ generation (Sun et al, 2003).…”

Section: Crosstalk Between Lpa and The Pathogenesis Of Alzheimer's DImentioning

confidence: 99%

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

Hao

Guo

Feng

et al. 2020

Front. Mol. Neurosci.

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Lysophospholipids (LPLs) are bioactive signaling lipids that are generated from phospholipase-mediated hydrolyzation of membrane phospholipids (PLs) and sphingolipids (SLs). Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two of the best-characterized LPLs which mediate a variety of cellular physiological responses via specific G-protein coupled receptor (GPCR) mediated signaling pathways. Considerable evidence now demonstrates the crucial role of LPA and S1P in neurodegenerative diseases, especially in Alzheimer's disease (AD). Dysfunction of LPA and S1P metabolism can lead to aberrant accumulation of amyloid-β (Aβ) peptides, the formation of neurofibrillary tangles (NFTs), neuroinflammation and ultimately neuronal death. Summarizing LPA and S1P signaling profile may aid in profound health and pathological processes. In the current review, we will introduce the metabolism as well as the physiological roles of LPA and S1P in maintaining the normal functions of the nervous system. Given these pivotal functions, we will further discuss the role of dysregulation of LPA and S1P in promoting AD pathogenesis.

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Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways

Cited by 450 publications

References 225 publications

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

The Interstitial System of the Brain in Health and Disease

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

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