Reduced cerebrospinal fluid levels of α-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits

Anderson, Jeffrey J.; Holtz, Greg; Baskin, Patricia; Wang, R.; Mazzarelli, Louis; Wagner, Steven L.; Menzaghi, Frédérique

doi:10.1016/s0306-4522(99)00244-4

Cited by 58 publications

(36 citation statements)

References 37 publications

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“…Exogenously applied APPsα has been shown to enhance LTP in hippocampal slices (45), and in behavioral paradigms, intracerebroventricularly administered APPsα enhanced memory in normal and amnesic mice (46). Furthermore, a positive association between cerebrospinal fluid levels of APPsα and cognitive performance in rats has been reported (47).…”

Section: Discussionmentioning

confidence: 97%

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Postina¹,

Schroeder²,

Dewachter³

et al. 2004

J. Clin. Invest.

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Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (a disintegrin and metalloproteinase) are the main candidates as physiologically relevant α-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP [V717I] increased the secretion of the neurotrophic soluble α-secretase-released N-terminal APP domain (APPsα), reduced the formation of Aβ peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD. 1456The

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Section: Discussionmentioning

confidence: 97%

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Postina¹,

Schroeder²,

Dewachter³

et al. 2004

J. Clin. Invest.

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“…Interestingly, both memory and LTP deficits that occur as a consequence of APP (and thus APPs␣) deficiency are age-dependent Seabrook et al, 1999), suggesting that compensatory mechanisms that may mask the APPs␣ deficit in young mice are lost during the aging process. Intriguingly, reduced APPs levels not only have been found in the CSF of aged rats, which correlated with spatial memory deficits (Anderson et al, 1999), but also were found to be reduced in the CSF of affected members of a familial case of AD (Almkvist et al, 1997). Moreover, reduced CSF levels of APPs␣, ␣-secretase ADAM10 protein level, and activity are prominent features of sporadic AD cases (Lannfelt et al, 1995;Sennvik et al, 2000;Colciaghi et al, 2002;Tyler et al, 2002).…”

Section: Discussionmentioning

confidence: 97%

The Secreted β-Amyloid Precursor Protein Ectodomain APPsα Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice

Ring¹,

Weyer²,

Kilian³

et al. 2007

J. Neurosci.

338

417

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It is well established that the proteolytic processing of the ␤-amyloid precursor protein (APP) generates ␤-amyloid (A␤), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPs␣) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APP⌬CT15). Interestingly, the ⌬CT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced A␤ levels in brain, likely because of reduced processing in the endocytic pathway. Most importantly, we demonstrate that in both APP knock-in lines the expression of APP N-terminal domains either grossly attenuated or completely rescued the prominent deficits of APP knock-out mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and long-term potentiation. Together, our data suggest that the APP C terminus is dispensable and that APPs␣ is sufficient to mediate the physiological functions of APP assessed by these tests.

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“…At 3, 12, 24, or 48 h later, subgroups of five rats from each treatment group were anesthetized with Halothane. CSF was collected as described previously (Anderson et al, 1999), and the left hemisphere of each brain was excised and immediately placed in 3.0 ml of extraction solvent (isopropanol-ethyl acetate-0.1 N HCl; 3:3:1) and 3.0 ml of distilled water. The brain samples were homogenized for 30 s then centrifuged at 1500g for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Wallace¹,

Muscará²,

Nucci³

et al. 2004

J Pharmacol Exp Ther

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NCX-2216 [3-[4-(2-fluoro-␣-methyl-[1,1Ј-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester] is anNO-releasing flurbiprofen derivative that also contains a ferulic acid (antioxidant) moiety. NCX-2216 has been shown to be effective in reducing ␤-amyloid deposition in a transgenic mouse model of Alzheimer's disease. The tolerability of this compound in the stomach and its ability to suppress prostaglandin synthesis in the brain are not known. The purpose of this study was to assess the contribution of nitric oxide (NO) and ferulic acid to the pharmacological properties of NCX-2216 versus flurbiprofen; thus, we compared their gastric tolerability and suppression of prostaglandin synthesis, peripherally and centrally. Oral flurbiprofen produced extensive gastric damage and suppressed gastric prostaglandin synthesis. In contrast, while suppressing prostaglandin production, equimolar doses of NCX-2216 did not cause detectable gastric injury. The NO-releasing moiety of NCX-2216 (but not the ferulic acid moiety) was crucial for the gastric safety of this compound. NCX-2216 substantially inhibited prostanoid synthesis despite not being detectable in plasma and despite producing only low amounts of flurbiprofen in plasma and in the brain. Inhibition of brain prostaglandin synthesis by NCX-2216 (22 mg/ kg) persisted for a much longer period of time (up to 48 h) than was seen with flurbiprofen (Յ12 h). These results demonstrate that a single administration of NCX-2216 can produce prolonged suppression of brain prostaglandin synthesis without causing gastric injury. It is likely that an active metabolite of NCX-2216 contributes to the suppression of cyclooxygenase activity. NCX-2216 may represent an attractive alternative to conventional nonsteroidal anti-inflammatory drugs for long-term treatment of a variety of inflammatory disorders, especially those occurring in the central nervous system.

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Reduced cerebrospinal fluid levels of α-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits

Cited by 58 publications

References 37 publications

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

The Secreted β-Amyloid Precursor Protein Ectodomain APPsα Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

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