Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease

Kawai, Mitsuru; Kalaria, Rajesh N.; Cras, Patrick; Siedlak, Sandra L.; Velasco, Manuel E.; Shelton, Earl R.; Chan, Hardy; Greenberg, Barry D.; Perry, George

doi:10.1016/0006-8993(93)90021-e

Cited by 184 publications

(130 citation statements)

References 19 publications

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“…Both caffeine and ryanodine cause calcium release within and contraction of vascular smooth muscle (Hisayama et al, 1990). Ultrastructural studies have shown that Aß is deposited within the outer basement membrane in the congophilic amyloid angiopathy of AD (Yamaguchi et al, 1992), and that it may be produced in the tunica media by proliferating or degenerating vascular smooth muscle cells (Kawai et al, 1993;Frackowiak et al, 1994). Intracellular Aß deposits occur outside the CNS in the uniquely human muscle disease, inclusion body myositis (Mendell et al, 1991;Askanas et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Caffeine Stimulates Amyloid β‐Peptide Release from β‐Amyloid Precursor Protein‐Transfected HEK293 Cells

Querfurth

Jiang²,

Geiger

et al. 1997

Journal of Neurochemistry

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Extracellular amyloid ß-peptide (Aß) deposition is a pathological feature of Alzheimer's disease and the aging brain. Intracellular Aß accumulation is observed in the human muscle disease, inclusion body myositis. Aß has been reported to be toxic to neurons through disruption of normal calcium homeostasis. The pathogenic role of Aß in inclusion body myositis is not as clear. Elevation of intracellular calcium following application of calcium ionophore increases the generation of Aß from its precursor protein (ßAPP). A receptor-based mechanism for the increase in Aß production has not been reported to our knowledge. Here, we use caffeine to stimulate ryanodine receptor (RYR)-regulated intracellular calcium release channels and show that internal calcium stores also participate in the genesis of Aß. In cultured HEK293 cells transfected with ßAPP cDNA, caffeine (5-10 mM) significantly increased the release of Aß fourfold compared with control. These actions of caffeine were saturable, modulated by ryanodine, and inhibited by the RYR antagonists ruthenium red and procaine. The calcium reuptake inhibitors thapsigargin and cyclopiazonic acid potentiated caffeine-stimulated Aß release. NH 4CI and monensin, agents that alter acidic gradients in intracellular vesicles, abolished both the caffeine and ionophore effects. Immunocytochemical studies showed some correspondence between the distribution patterns of RYR and cellular ßAPP immunoreactivities. The relevance of these findings to Alzheimer's disease and inclusion body myositis is discussed. Key Words: CaffeineAmyloid ß-peptide-ß-Amyloid precursor protein-HEK293 cells-Alzheimer's disease-Inclusion body myositis. J. Neurochem. 69, 1580-1591 (1997).ß-Amyloid-laden plaques and vascular deposits are pathologic hallmarks common to Alzheimer' s disease (AD) and the normal aging process. The 4-kDa amybid ß-peptide (Aß) is a secreted 39-42 amino acid peptide by-product of endocytotic and secretory processes (involving unidentified proteases referred to as ß-and y-secretases) acting on the ß-amyloid precursor protein (ßAPP) . The predominant proteolytic event of ßAPP processing leads to the secretion of a large NH2-terminal ectodomain (ßPP5) (Weidemann et al., 1989;Esch et al., 1990;Sisodia et al., 1990) and retention of a 10-kDa COOHterminal membrane fragment (Selkoe et al., 1988) that is catalyzed by an unknown protease termed a-secretase. The latter scission occurs at Aß position 16, thereby precluding formation of intact Aß (Esch et al., 1990;Oltersdorf et al., 1990), and occurs either at the cell surface or within secretory vesicles targeted for exocytosis (Sisodia et al., 1990;Sambamurti et al., 1992;De Strooper et al., 1993; Haass et al., 1995b). A second trafficking pathway involves the reinternalization of cell surface ßAPP by endosomes that are ultimately targeted to lysosomes (Yamazaki et al., 1995). Constitutive production of Aß from wild-type ßAPP molecules occurs mainly via endocytosis of cell surface-associated ßAPP (Koo and Squazzo, 1994).Aß deposits ...

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Section: Discussionmentioning

confidence: 99%

Caffeine Stimulates Amyloid β‐Peptide Release from β‐Amyloid Precursor Protein‐Transfected HEK293 Cells

Querfurth

Jiang²,

Geiger

et al. 1997

Journal of Neurochemistry

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“…These degenerating smooth muscle cells have been implicated in the overproduction of A␤PP and A␤ in the cerebral vessel wall further suggesting the active involvement of these cells in the progression of this cerebrovascular pathology (17)(18)(19). Similar to these in vivo observations, we have reported that A␤- , the more pathogenic form of the wild-type peptide, causes severe cellular degeneration accompanied by a marked increase in the level of cell-associated A␤PP in cultured human cerebrovascular smooth muscle (HCSM) cells (20 -22).…”

Section: Fibrillar Amyloid-␤ Protein (A␤)mentioning

confidence: 99%

Localization of a Fibrillar Amyloid β-Protein Binding Domain on Its Precursor

Nostrand

Melchor²,

Keane

et al. 2002

Journal of Biological Chemistry

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Fibrillar amyloid-␤ protein (A␤)1 deposition in senile plaques in the neuropil and in the walls of cerebral blood vessels is a common pathologic feature of patients with Alzheimer's disease (AD) and certain related disorders including Down's syndrome and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (1). A␤ is a 39 -43-amino acid peptide that has the propensity to self-assemble into insoluble, ␤-sheet-containing fibrils (1, 2). A␤ is proteolytically derived from a large type I integral membrane precursor protein, termed the amyloid ␤-protein precursor (A␤PP), encoded by a gene located on chromosome 21 (3-6). In this regard, full-length A␤PP is proteolytically cleaved by an enzyme, termed ␤-secretase, at the amino terminus of the A␤ domain. A novel aspartyl proteinase named BACE (for ␤-site A␤PP-Cleaving Enzyme) has been identified as the ␤-secretase enzyme (7-10). Subsequent cleavage of the remaining amyloidogenic membrane spanning A␤PP carboxyl-terminal fragment by an enzyme termed ␥-secretase liberates the 40-or 42-amino acid residue A␤ peptide. Although the exact identity of ␥-secretase remains unclear studies suggest that the presenilin proteins may function as this enzyme or as a required cofactor for ␥-secretase function (11-13). Alternatively, full-length A␤PP can be proteolytically processed by an enzyme termed ␣-secretase through the A␤ domain. This cleavage event generates a non-amyloidogenic membrane spanning carboxyl-terminal fragment and truncated secretory forms of A␤PP␣ (sA␤PP␣) that are released into the extracellular environment (14,15).Cerebrovascular A␤ deposition, known as cerebral amyloid angiopathy, is accompanied by smooth muscle cell degeneration suggesting a toxic effect of A␤ to these cells in vivo (16 -18). These degenerating smooth muscle cells have been implicated in the overproduction of A␤PP and A␤ in the cerebral vessel wall further suggesting the active involvement of these cells in the progression of this cerebrovascular pathology (17-19). Similar to these in vivo observations, we have reported that A␤-(1-42), the more pathogenic form of the wild-type peptide, causes severe cellular degeneration accompanied by a marked increase in the level of cell-associated A␤PP in cultured human cerebrovascular smooth muscle (HCSM) cells (20 -22). In more recent studies we demonstrated that mutations associated with familial forms of cerebral amyloid angiopathy (E22Q Dutch, E22K Italian, and D23N Iowa) markedly enhance both the fibrillogenic and cerebrovascular pathogenic properties of A␤ toward cultured HCSM cells (23)(24)(25)(26). These experiments showed that these pathogenic forms of A␤ assemble into an

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“…Several ultrastructural or imrnunohistochemical studies have demonstrated that endothelial cells, pericytes and smooth muscle cells (43,53,54) un dergo degeneration in amyloid-laden vessels. Sharply in contrast with the effects of synthetic Ap peptijdes on neu rons are the effects on cultured vascular cells.…”

Section: Verbeek Et Almentioning

confidence: 99%

Differences between the Pathogenesis of Senile Plaques and Congophilic Angiopathy in Alzheimer Disease

Verbeek

Eikelenboom

Waal

1997

Journal of Neuropathology and Experimental Neurology

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Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease

Cited by 184 publications

References 19 publications

Caffeine Stimulates Amyloid β‐Peptide Release from β‐Amyloid Precursor Protein‐Transfected HEK293 Cells

Caffeine Stimulates Amyloid β‐Peptide Release from β‐Amyloid Precursor Protein‐Transfected HEK293 Cells

Localization of a Fibrillar Amyloid β-Protein Binding Domain on Its Precursor

Differences between the Pathogenesis of Senile Plaques and Congophilic Angiopathy in Alzheimer Disease

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