Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer’s β-amyloid protein precursor in the brain. Brain Res 649: 323-328
Department of Neuropathology, Polish Academy of Sciences, Warsaw. Brain Research
(Impact Factor: 2.84).
07/1994; 649(1-2):323-8. DOI: 10.1016/0006-8993(94)91081-2
The distribution of beta-amyloid protein precursor (APP) was investigated immunocytochemically in rats subjected to global cerebral ischemia (GCI) induced by cardiac arrest. Rats underwent 10 min of GCI with 3, 6, and 12 h and 2 and 7 days of survival. APP immunostaining was found extracellular and intracellularly. Multiple extracellular APP immunoreactive deposits around and close to the vessels appeared as soon as 3 h after GCI. Extracellular accumulation of APP occurred frequently in the hippocampus, cerebral and cerebellar cortex, basal ganglia and thalamus and rarely in the brain stem. These deposits were labelled with antibodies against the N-terminal, beta-amyloid peptide, and C-terminal domains of APP. Our data suggests that either proteolytically cleaved fragments of the full-length APP or the entire APP molecule accumulates extracellularly after GCI. This findings may not only implicate the participation of APP in postischemic tissue damage but also suggest the involvement of pathomechanisms operating in ischemia in Alzheimer's disease pathology.
Available from: Anna Bogucka-Kocka
- "In contrast to classical view of sporadic Alzheimer’s disease, recent data indicate that ischemia–reperfusion injury contributes to progressing degeneration in Alzheimer’s disease [4, 6, 13, 14, 23–25, 27, 28, 183]. We suggest that the ischemic blood–brain barrier maturation hypothesis of Alzheimer’s disease implying that pathological permeability and faulty clearance of β-amyloid peptide across the ischemic blood–brain barrier could act as seeds for the process that is responsible for β-amyloid peptide accumulation as plaques and maturation in Alzheimer’s disease neurodegeneration progression [30, 36, 90, 160, 166–168, 170, 181]. "
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ABSTRACT: The study of sporadic Alzheimer's disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer's disease, the basis of this entity is not yet clear. At present, the best-established and accepted "culprit" in Alzheimer's disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the "amyloid hypothesis." We will critically review these observations and highlight inconsistencies between the predictions of the "amyloid hypothesis" and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer's disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer's disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer's disease. The identification of the genes involved in Alzheimer's disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer's disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer's disease.
Molecular Neurobiology 03/2013; 48(3). DOI:10.1007/s12035-013-8439-1 · 5.14 Impact Factor
Available from: Ryszard Maciejewski
- "This is followed by a significant increase of intracellular β-amyloid peptide as well as by functional and morphological signs of apoptotic neuronal death  (Fig. 1). The amyloidogenic processing of the amyloid precursor protein by β-secretase is important to β-amyloid peptide plaque development in the ischemic brain [14–16, 19, 21, 50] and Alzheimer’s disease . Current data showed that an experimental brain ischemia generates the overexpression, production, and activity of Alzheimer’s disease β-secretase [51–54] (Fig. 1). "
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ABSTRACT: Amyloid precursor protein cleavage through β- and γ-secretases produces β-amyloid peptide, which is believed to be responsible for death of neurons and dementia in Alzheimer's disease. Levels of β- and γ-secretase are increased in sensitive areas of the Alzheimer's disease brain, but the mechanism of this process is unknown. In this review, we prove that brain ischemia generates expression and activity of both β- and γ-secretases. These secretases are induced in association with oxidative stress following brain ischemia. Data suggest that ischemia promotes overproduction and aggregation of β-amyloid peptide in brain, which is toxic for ischemic neuronal cells. In our review, we demonstrated the role of brain ischemia as a molecular link between the β- and the γ-secretase activities and provided a molecular explanation of the possible neuropathogenesis of sporadic Alzheimer's disease.
Molecular Neurobiology 10/2012; 47(1). DOI:10.1007/s12035-012-8360-z · 5.14 Impact Factor
Available from: onlinelibrary.wiley.com
- "Patients with AD have often a history of various infections and AD often coexists with cerebrovascular abnormalities. Ischemic injury increases the expression of APP (Kalaria et al., 1993; Koistinaho et al., 1996; Nihashi et al., 2001; Pluta et al., 1994), the source of cleaved Ab peptides and b-secretase1 (Wen et al., 2004), a b-site of APP cleaving enzyme leading to extracellular accumulation of Ab, which may persist up to several months after ischemia (van Groen et al., 2005). Similarly to stroke, also head trauma may be a risk factor for AD (reviewed in Van Den Heuvel et al., 2007). "
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ABSTRACT: Alzheimer's disease (AD) is a dementing neurodegenerative disorder without a cure. The abnormal parenchymal accumulation of beta-amyloid (Abeta) is associated with inflammatory reactions involving microglia and astrocytes. Increased levels of Abeta and Abeta deposition in the brain are thought to cause neuronal dysfunction and underlie dementia. Microglia, the brain resident cells of monocytic origin, have a potential ability to phagocytose Abeta but they also react to Abeta by increased production of proinflammatory toxic agents. Microglia originate from hemangioblastic mesoderm during early embryonic stages and from bone marrow (BM)-derived monocytic cells that home the brain throughout the neonatal stage of development. Recent studies indicate that BM or blood-derived monocytes are recruited to the diseased AD brain, associate with the Abeta depositions, and are more efficient phagocytes of Abeta compared with resident microglia. The clearance of Abeta deposition by these cells has been recently under intensive investigation and can occur through several different mechanisms. Importantly, peripheral monocytic cells of patients with AD appear to be deficient in clearing Abeta. This review will summarize the findings on the role of blood-derived cells in AD and discuss their therapeutic potential for treating patients suffering from this devastating disease.
Glia 06/2010; 58(8):889-900. DOI:10.1002/glia.20973 · 6.03 Impact Factor
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