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Extracellular deposits of Abeta produced in cultures of Alzheimer disease brain vascular smooth muscle cells. J Neuropathol Exp Neurol

NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 4.37). 02/2005; 64(1):82-90.
Source: PubMed

ABSTRACT Alzheimer disease (AD) and Down syndrome (DS) brains contain deposits of amyloid-beta peptide that are located extracellularly in the neuropil and in blood vessels walls. A small fraction of brain Abeta is detected intracellularly in neurons, smooth muscle cells, and microglia. The roles of these extracellular and intracellular pools of Abeta in pathogenesis of AD-type dementia are controversial. Cell culture models of vascular amyloidosis-beta revealed intracellular, but not extracellular deposition of Abeta. Here we demonstrate for the first time, formation of extracellular deposits of Abeta in primary cultures of vascular smooth muscle cells isolated from AD cases with cerebrovascular amyloid angiopathy. Extracellular Abeta deposition required the use of cultures that produced high quantities of Abeta, which contained at least 50% of cells forming intracellular Abeta deposits, and providing extracellular matrix proteins. During 12 days of culture in this system, we observed accumulation of nonfibrillar, granular deposits in extracellular matrix, similar to early stages of vascular amyloidogenesis in vivo. This is a valuable system to study the effects of various potential amyloidogenic factors on formation of extracellular Abeta deposits.

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    • "Amyloid deposition, one of the pathologic hallmarks of AD, is found in tissues outside the CNS [8]. Although skeletal muscle was initially not found as a site of amyloid deposition, a later study showed detectable amyloid beta 42 (Aβ42) in skeletal muscle in normal elderly, and significant evaluations in autopsy AD muscle [9,10]. "
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    • "A local activation of microglial cells is consistently detected in the brains of patients with Alzheimer's disease (AD), but the role of activated peripheral myeloid cells in the pathogenesis of AD has not been resolved (Akiyama et al., 2000; Prinz and Mildner, 2011). For example, microglial cells have been suggested to be responsible for pathological ␤-amyloid (A␤) protein deposition (Wisniewski et al., 1989; Akiyama et al., 2000; Frackowiak et al., 2005), but at the same time, they have also been implicated in A␤ clearance (Chung et al., 1999; Bard et al., 2000; Wyss-Coray et al., 2001; Jantzen et al., 2002). Moreover, it has been shown recently that the interaction of CD40 with CD40 ligand on the surface of microglia is an important molecular signal for microglia activation in AD mouse models (Tan et al., 1999, 2002; Gate et al., 2010). "
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    • "The involvement of VSMCs in the production of Aß was already hypothesized following the early observation that Aß deposits are closely associated with cerebral VSMCs (Frackowiak et al., 1994) and the presence of APP and Aß in VSMCs (Coria et al., 1992; Davis-Salinas and Van Nostrand, 1995; Frackowiak et al., 2004; Wisniewski et al., 1995). However, several facts have rested relevance to the contribution of VSMCs to CAA: (1) most reports just mention intracellular Aß accumulation in VSMCs (Wisniewski et al., 1995), (2) absence of Aß 1–42 production by primary cultures of VSMCs (Frackowiak et al., 2005) and (3) the lack of a mechanism linking the production of Aß in VSMCs to the etiopathology of AD. Neuronal APP can be cleaved by two different pathways . "
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