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.
"Amyloid deposition, one of the pathologic hallmarks of AD, is found in tissues outside the CNS . 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]. "
[Show abstract][Hide abstract] ABSTRACT: Age is considered a primary risk factor for neurodegenerative diseases including Alzheimer's disease (AD). It is also now well understood that mitochondrial function declines with age. Mitochondrial deficits have been previously assessed in brain from both human autopsy tissue and disease-relevant transgenic mice. Recently it has been recognized that abnormalities of muscle may be an intrinsic aspect of AD and might contribute to the pathophysiology. However, deficits in mitochondrial function have yet to be clearly assessed in tissues outside the central nervous system (CNS). In the present study, we utilized a well-characterized AD-relevant transgenic mouse strain to assess mitochondrial respiratory deficits in both brain and muscle. In addition to mitochondrial function, we assessed levels of transgene-derived amyloid precursor protein (APP) in homogenates isolated from brain and muscle of these AD-relevant animals.
We now demonstrate that skeletal muscles isolated from these animals have differential levels of mutant full-length APP depending on muscle type. Additionally, isolated muscle fibers from young transgenic mice (3 months) have significantly decreased maximal mitochondrial oxygen consumption capacity compared to non-transgenic, age-matched mice, with similar deficits to those previously described in brain.
This is the first study to directly examine mitochondrial function in skeletal muscle from an AD-relevant transgenic murine model. As with brain, these deficits in muscle are an early event, occurring prior to appearance of amyloid plaques.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP(swe/PS1), APP(swe), and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to β-amyloid (Aβ) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Aβ load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired β-amyloid clearance and amplified vascular Aβ deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2011; 31(31):11159-71. DOI:10.1523/JNEUROSCI.6209-10.2011 · 6.34 Impact Factor
"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 . "
[Show abstract][Hide abstract] ABSTRACT: Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid ss-peptide (Ass) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work, we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ss-protein precursor (APP) cleavage and produce Ass(1-40) and Ass(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ss-site APP cleaving enzyme 1 (BACE1) expression, as well as Ass(1-40) and Ass(1-42) secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients.
Neurobiology of aging 08/2008; 29(7):969-80. DOI:10.1016/j.neurobiolaging.2007.01.009 · 5.01 Impact Factor
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