Amyloid precursor protein mRNA levels in Alzheimer's disease brain

Preece, Paul; Virley, David; Costandi, Moheb; Coombes, Robert; Moss, Stephen J.; Mudge, Anne W.; Jazin, Elena; Cairns, Nigel J.

doi:10.1016/j.molbrainres.2003.08.022

Cited by 47 publications

(30 citation statements)

References 46 publications

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“…Indeed, a number of reports indicate that the amount of APP mRNA is increased in autopsied brains of AD patients (Moir et al, 1998;Preece et al, 2004;Matsui et al, 2007) and it is remarkable that overproduction of APP in Down's syndrome leads to clinical AD pathology several years earlier than in the general population (Bush and Beail, 2004;Head et al, 2007). Products derived from APP metabolism, other that Aβ peptide, in particular CTFs such as C83, C99 and AICD, could play a crucial pathological role in AD (Rockenstein et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Simón

Schiapparelli

Salazar-Colocho

et al. 2009

Neurobiology of Disease

100

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Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP wt ) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ 42 ) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ 42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Simón

Schiapparelli

Salazar-Colocho

et al. 2009

Neurobiology of Disease

100

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“…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). These data show that A␤ levels and amyloid plaque load, in both familial and sporadic AD, are extremely sensitive to alterations in APP mRNA and protein levels, and that small changes can accumulate over time to profoundly effect disease.…”

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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“…In the brain, both are expressed in glial cells, whereas APP695 is abundant in neurons (LeBlanc et al, 1991). Neuronal expression of KPI-APP exhibits an important amyloidogenic potential (Ho et al, 1996), and APP770 mRNA is significantly elevated in the brain of AD patients (Rockenstein et al, 1995;Moir et al, 1998;Preece et al, 2004). Thus, a shift from APP695 to KPI-APP neuronal expression may result in a higher production of A␤ in the brain parenchyma.…”

Section: Introductionmentioning

confidence: 99%

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

Bordji¹,

Becerril-Ortega²,

Nicole³

et al. 2010

J. Neurosci.

167

147

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Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of ␤-amyloid (A␤), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal A␤ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of A␤. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal A␤ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/ calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal A␤ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal A␤ release, representing a causal risk factor for developing AD.

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Amyloid precursor protein mRNA levels in Alzheimer's disease brain

Cited by 47 publications

References 46 publications

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

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

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

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