ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes

Keable, Abby; O’Neill, Ronan; Sharp, Matthew MacGregor; Gatherer, Maureen; Yuen, Ho Ming; Johnston, D.; Weller, Roy O.; Carare, Roxana O.

doi:10.3390/ijms21124371

Cited by 10 publications

(5 citation statements)

References 44 publications

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“…This binding is weaker for APOE ε4‐Aβ than APOE ε3‐Aβ complexes [ 212 ]. Astrocytes from ε4‐positive individuals secreted less laminin and collagen IV, and more fibronectin when forming the CVBM [ 213 ]. Conversely, ECM laminin and collagen were increased in ε2 carriers [ 214 ].…”

Section: Alterations In the Cerebral Vascular Basement Membrane In Admentioning

confidence: 99%

Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives

2022

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Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non-amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit -particularly of endothelial cells and pericytes -and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance -both intra-periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi-directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD. K E Y W O R D SAlzheimer's disease, blood-brain barrier, cerebral blood flow, neurovascular coupling, pericyte, vasculature How to cite this article: Fisher RA, Miners JS, Love S. Pathological changes within the cerebral vasculature in Alzheimer's disease: New perspectives.

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Section: Alterations In the Cerebral Vascular Basement Membrane In Admentioning

confidence: 99%

Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives

2022

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“…In other work examining ECM changes with APOE4, Keable et al found that astrocytes cultured from KI APOE4 mice pups secreted significantly greater amount of fibronectin than KI APOE3 astrocytes and that increased fibronectin could enhance Aβ aggregation in the cerebral microvasculature (Keable et al, 2020). Of interest is that APOE4 murine microglia exhibit significantly increased SERPINA3 mRNA than APOE3 murine microglia that was found in two separate studies (Machlovi et al, 2022;Sepulveda et al, 2022).…”

Section: Ecm Changes In Apoe4mentioning

confidence: 92%

Matrix disequilibrium in Alzheimer’s disease and conditions that increase Alzheimer’s disease risk

et al. 2023

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Alzheimer’s Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

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“…ApoE, particularly apoE4, may impair IPAD-mediated clearance of A␤ [292]. ApoE4-expressing astrocytes secrete more fibrinectin and less laminin than apoE3-expressing astrocytes, promoting aggregation of A␤ on cere-brovascular basement membranes [293]. In CAA, apoE co-localizes with A␤ [294][295][296].…”

Section: Intramural Periarterial Drainage (Ipad) Clearance Of A␤mentioning

confidence: 99%

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems

Loeffler

2024

JAD

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Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer’s disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a “peripheral sink” mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

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ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes

Cited by 10 publications

References 44 publications

Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives

Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives

Matrix disequilibrium in Alzheimer’s disease and conditions that increase Alzheimer’s disease risk

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems

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