Agrin and microvascular damage in Alzheimer's disease

Peck, Jason A.; Stopa, Edward G.

doi:10.1016/s0197-4580(00)82917-6

Cited by 26 publications

(31 citation statements)

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“…Heparan sulfate proteoglycans such as fibronectin and perlecan provide stability and flexibility to the basement membrane, accelerating the aggregation of Ab by high-affinity interactions (Castillo et al, 1997;Cotman et al, 2000). In AD brains, the levels of heparan sulfate proteoglycans are increased compared with agematched controls (Berzin et al, 2000;Shimizu et al, 2009). In this study in the mouse, we found that the levels of collagen IV was significantly decreased in the cortex and in the hippocampus, but not in the striatum and thalamus of aged mice.…”

Section: Discussionmentioning

confidence: 52%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

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Section: Discussionmentioning

confidence: 52%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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“…Damage of astrocytic processes after activation of apoptotic pathways and cleavage of cytoskeletal proteins, such as GFAP as demonstrated in the present study, may be one of many factors that contribute to the compromised blood-brain barrier observed in AD. 21,41 In summary, caspase-mediated cleavage of GFAP, activation of caspase-3, and damage to astrocytes were common features found together in the AD brain. The link between reactive gliosis, caspase activation, and cytoskeletal protein cleavage may arise from extracellular A␤ acting to stimulate the activation of apoptotic pathways within astrocytes.…”

Section: Discussionmentioning

confidence: 90%

Caspase-Mediated Cleavage of Glial Fibrillary Acidic Protein within Degenerating Astrocytes of the Alzheimer's Disease Brain

Mouser

Head

et al. 2006

The American Journal of Pathology

112

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Recent studies demonstrate roles for activation of caspases and cleavage of cellular proteins within neurons of the Alzheimer's disease (AD) brain. To determine whether a similar role for caspases also occurs within glial cells in AD, we designed a site-directed caspase-cleavage antibody specific to glial fibrillary acidic protein (GFAP), a cytoskeleton protein specifically expressed in astrocytes. In vitro characterization of this antibody using both a cell-free system and a cell model system of apoptosis demonstrated that the antibody (termed GFAP caspase-cleavage product antibody or GFAP-CCP Ab) immunolabeled the predicted caspase-cleavage fragment, but not full-length GFAP, by Western blot analysis. To determine whether caspases cleave GFAP in vivo, tissue sections from control and AD brains were examined by immunohistochemistry using the GFAP-CCP Ab. Two prominent features of staining were evident: immunolabeling of degenerating astrocytes in proximity to blood vessels and staining within plaque-rich regions of the AD brain. Furthermore, co-localization of the GFAP-CCP Ab and an antibody specific to active caspase-3 was demonstrated within damaged astrocytes of the AD brain. These data suggest that the activation of caspases and cleavage of cellular proteins such as GFAP may contribute to astrocyte injury and damage in the AD brain.

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“…51-53; for review, see Ref. 54) via a rather leaky BBB (55,56). Their numbers, however, can be lower than those found in the neurodegenerative disorders multiple sclerosis and experimental autoimmune encephalitis, in which the CNS is severely injured and the BBB is disrupted.…”

Section: Pathophysiological Significance Of Il-4-induced A␤ Clearancementioning

confidence: 99%

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Shimizu

Kawahara

Kajizono

et al. 2008

The Journal of Immunology

130

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A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ1–42 (o-Aβ1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125I-labeled o-Aβ1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.

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Agrin and microvascular damage in Alzheimer's disease

Cited by 26 publications

References 0 publications

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Caspase-Mediated Cleavage of Glial Fibrillary Acidic Protein within Degenerating Astrocytes of the Alzheimer's Disease Brain

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

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