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- Lord, Anna, 1979-, et al.
(författare)
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Amyloid-β protofibril levels correlate with spatial learning in Arctic Alzheimer’s disease transgenic mice
- 2009
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 276:4, s. 995-1006
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Tidskriftsartikel (refereegranskat)abstract
- Oligomeric assemblies of amyloid-β (Aβ) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Aβ correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Aβ species have been shown to be neurotoxic, to interfere with learned behavior and to inhibit the maintenance of hippocampal long-term potentiation. The tg-ArcSwe model (i.e. transgenic mice with the Arctic and Swedish Alzheimer mutations) expresses elevated levels of Aβ protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these Aβ assemblies. In the present study, we estimated Aβ protofibril levels in the brain and cerebrospinal fluid of tg-ArcSwe mice, and also assessed their role with respect to cognitive functions. Protofibril levels, specifically measured with a sandwich ELISA, were found to be elevated in young tg-ArcSwe mice compared to several transgenic models lacking the Arctic mutation. In aged tg-ArcSwe mice with considerable plaque deposition, Aβ protofibrils were approximately 50% higher than in younger mice, whereas levels of total Aβ were exponentially increased. Young tg-ArcSwe mice showed deficits in spatial learning, and individual performances in the Morris water maze were correlated inversely with levels of Aβ protofibrils, but not with total Aβ levels. We conclude that Aβ protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extent than total Aβ. Our findings suggest that increased levels of Aβ protofibrils could result in spatial learning impairment.
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| 2. |
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| 3. |
- Lord, Anna, 1979-, et al.
(författare)
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Arctic Aβ selectively increases diffuse deposition of wild type Aβ in APP transgenic mice with the Swedish mutation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Studies of familial Alzheimer´s disease (AD) suggest that misfolding and aggregation of amyloid-β (Aβ) peptides initiate the pathogenesis, which causes dementia. The Arctic amyloid precursor protein (APP) mutation results in AD, and Arctic Aβ is more prone to form Aβ protofibrils. Here we show that the number of diffuse Aβ deposits, but not amyloid plaques, is increased if tg-ArcSwe mice synthesizing a low level of Arctic Aβ are crossed with plaque-depositing tg-Swe mice. The diffuse deposits in bitransgenic mice, which contain mainly wild type Aβ42, accumulate in regions both with and without transgene expression. The selective increase of a single type of parenchymal Aβ deposit suggest that different pathways of Aβ aggregation lead to the formation of diffuse and compact Aβ deposits in the brain. The raise in diffuse deposits is most likely due to direct physical interactions between Arctic and wild type Aβ42, and not to altered APP processing in young bitransgenic mice. A mixture of Arctic and wild type Aβ42 facilitates the formation of prefibrillar and fibrillar Aβ assemblies, but inhibits the further elongation of Aβ fibrils in vitro. Our findings might have implications to the pathogenesis of patients who are heterozygous for the Arctic mutation. It also further illustrates how Aβ neuropathology can be manipulated in vivo in a manner reminiscent to prion disorders.
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| 4. |
- Lord, Anna, 1979-
(författare)
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Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-β (Aβ) peptides more prone to form Aβ protofibrils. The aims of this thesis were to investigate the mechanisms of the Arctic mutation in vivo, and to use transgenic models to determine the role of early intermediates of Aβ aggregation, like protofibrils, in the pathogenesis. In addition, we aimed to evaluate protofibrils as a therapeutic target.Transgenic models with Arctic and Swedish mutations (tg-ArcSwe), and with the Swedish mutation alone (tg-Swe) were created. The Arctic mutation favored amyloidogenic processing of amyloid-β precursor protein (APP) in transgenic mice and cultured cells. The observed shift in the subcellular location and processing of APP led to increased production of intracellular Aβ in vitro, and also partly explained the early accumulation of intraneuronal Aβ in tg-ArcSwe mice. The intraneuronal Aβ in combination with enhanced levels of protofibrils appeared long before extracellular plaques emerged. Elevated protofibril levels were associated with intraneuronal Aβ and linked to spatial learning deficits in young mice, suggesting that protofibrils cause AD-related cognitive deficits. The Arctic mutation also enhanced senile plaque pathology in aged tg-ArcSwe mice, and the accelerated plaque deposition was accompanied by decreased intraneuronal Aβ. This suggests a dynamic equilibrium between the early accumulation of intraneuronal Aβ and the later senile plaque pathology.Aβ protofibrils were evaluated as a therapeutic target in tg-ArcSwe mice with passive immunization using a protofibril-selective antibody. This treatment cleared protofibrils without removing senile plaques. However, plaque formation was prevented if treatment began early, indicating that protofibrils are intermediate species of Aβ fibrillization in vivo. Targeting senile plaques with immunotherapy requires early diagnosis and intervention, whereas protofibrils can be specifically cleared from brain despite substantial AD-like deposition of insoluble Aβ. The early and persistent presence of protofibrils throughout Aβ amyloidosis makes them a promising target for future diagnostic and therapeutic strategies in AD.
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| 5. |
- Philipson, Ola, 1979-, et al.
(författare)
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Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The clinical symptoms associated with the Arctic (E693G) mutation in the amyloid-β precursor protein (APP) are those of typical Alzheimer’s disease (AD), beginning with insidious loss of recent memories. However, an unusual neuropathology of ring-like amyloid-β (Aβ) plaques is identified in postmortem brain. Here, the neuropathology of subjects carrying the Arctic mutation was compared to that of sporadic AD. Different types of Aβ-deposits were examined with light, confocal and electron microscopy, and their composition was analyzed with biochemical techniques. Parenchymal deposits of the Arctic mutant brain were homogenous in structure, lacked an amyloid core and were immunostained differentially by antibodies recognizing C- or N-terminal epitopes of Aβ. Superficially, Arctic Aβ plaques bore considerable resemblance to cotton wool plaques (CWP), namely their large size, the presence of healthy neuronal nuclei and the absence of marked neuritic dystrophy within the plaques, and the sparsity of astro- or microgliosis in the surrounding tissue. Both parenchymal deposits and cerebral amyloid angiopathy of Arctic mutant brain contained a mixture of Arctic and wild-type Aβ. While Aβ peptides in parenchymal plaques were often N-terminally truncated, a substantial amount of full-length Aβ1-40 was deposited in the vessel walls as cerebral amyloid angiopathy (CAA). Thus, the absence of amyloid cores in parenchymal plaques of Arctic mutant brain was likely due to the scarcity of full-length Aβ species, although other mechanisms could also be involved. Our findings are discussed in relation to the clinical features of patients carrying the Arctic mutation and neuropathological observations made with other intra-Aβ mutations in human and transgenic mouse brain.
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