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Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice.

ABSTRACT: Oligomeric assemblies of amyloid-beta (Abeta) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Abeta correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Abeta 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 Abeta protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these Abeta assemblies. In the present study, we estimated Abeta 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, Abeta protofibrils were approximately 50% higher than in younger mice, whereas levels of total Abeta 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 Abeta protofibrils, but not with total Abeta levels. We conclude that Abeta protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extent than total Abeta. Our findings suggest that increased levels of Abeta protofibrils could result in spatial learning impairment.

SUBMITTER: Lord A

PROVIDER: S-EPMC2752010 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice.

Lord Anna A Englund Hillevi H Söderberg Linda L Tucker Stina S Clausen Fredrik F Hillered Lars L Gordon Marcia M Morgan Dave D Lannfelt Lars L Pettersson Frida E FE Nilsson Lars N G LN

The FEBS journal 20090201 4

Oligomeric assemblies of amyloid-beta (Abeta) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Abeta correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Abeta 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 ...[more]

PMID: 19215301

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Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

Dataset Information

Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice.

Publications

Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice.

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