Expression of APP pathway mRNAs and proteins in Alzheimer’s disease

Matsui, Toshifumi; Ingelsson, Martin; Fukumoto, Hiroaki; Ramasamy, Karunya; Kowa, Hisatomo; Frosch, Matthew P.; Irizarry, Michael C.; Hyman, Bradley T.

doi:10.1016/j.brainres.2007.05.050

Cited by 159 publications

(127 citation statements)

References 45 publications

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“…These individuals develop extracellular plaques 20 -30 years earlier than normal individuals (Wisniewski et al, 1985). Additionally, APP mRNA and protein levels have been shown to be elevated in sporadic AD, correlating with elevated sAPP␣ and soluble A␤ (Matsui et al, 2007). Certain APP mRNA splice variants have also been shown to be specifically elevated in AD brains (Rockenstein et al, 1995;Preece et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Shineman¹,

Zhang²,

Leight³

et al. 2008

J. Neurosci.

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Alzheimer's disease (AD) amyloid plaques are composed of amyloid-␤ (A␤) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like A␤ brain pathology. To determine whether isoprostanes increase A␤ production, we delivered isoprostane iPF 2␣ -III into the brains of Tg2576 mice. Although treated mice showed increased brain A␤ levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF 2␣ -III on A␤. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased A␤ and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for ␣ and ␤ secretase proteolytic cleavages, thereby increasing A␤ generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble A␤, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.

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Section: Discussionmentioning

confidence: 99%

Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Shineman¹,

Zhang²,

Leight³

et al. 2008

J. Neurosci.

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“…In addition, there are numerous studies reporting increased APP expression in reactive astrocytes induced by different insults, such as lesions or injury of the hippocampus (4,33,34), heterotopic transplantation (35), cerebral artery occlusion (36), needle stab injury (14), cuprizone intoxication (37), kainic acidinduced neurotoxic damage (38), and exposure to A␤ peptides (39). Increased APP expression in astrocytes was also suggested to contribute to A␤ plaque deposition and AD pathogenesis (4,40). We show here that under basal conditions, we could not detect astroglial APP staining in primary cultures or in brain sections.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Precursor Protein Revisited

Guo

Gaddam

et al. 2012

Journal of Biological Chemistry

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“…Several isoforms of AβPP exist due to alternative splicing, with AβPP695 predominately expressed in neurons. However, in sporadic AD (sAD), two reports reveal a ratio shift towards the neuronal expression of AβPP isoforms other than AβPP695 [31,32], and additional reports indicate alterations in AβPP expression in platelets of AD individuals [33][34][35]. In addition to alternative splicing, AβPP may be truncated on the carboxyl end to form smaller and less amyloidogenic fragments.…”

Section: Amyloid Cascade Hypothesis: Mechanisms and Therapeutics For mentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.

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Expression of APP pathway mRNAs and proteins in Alzheimer’s disease

Cited by 159 publications

References 45 publications

Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Amyloid Precursor Protein Revisited

The Mitochondrial Secret(ase) of Alzheimer's Disease

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