Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content

Hamid, Runa; Kilger, Ellen; Willem, Michael; Vassallo, Neville; Kostka, Marcus; Bornhövd, Carsten; Reichert, Andreas S.; Kretzschmar, Hans A.; Haass, Christian; Herms, Jochen

doi:10.1111/j.1471-4159.2007.04627.x

Cited by 58 publications

(53 citation statements)

References 47 publications

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“…Expression of full length APP, for instance, affects spontaneous Ca 2ϩ oscillations in cultured neurons (22,23). Effects on intracellular Ca 2ϩ stores, on the other hand, have been attributed to the APP cleavage product AICD (24,25). Perhaps most intriguingly of all, however, are the effects mediated directly by the interaction of A␤ with Ca 2ϩ -permeable channels.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Zeiger

Vetrivel

Buggia-Prévot

et al. 2013

Journal of Biological Chemistry

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Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Zeiger

Vetrivel

Buggia-Prévot

et al. 2013

Journal of Biological Chemistry

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“…Recent findings highlight the importance of APP in synaptogenesis (73) and synaptic plasticity (14,29,61,64,77). Transgenic mice that overexpress wild-type (WT) APP exhibit enhanced memory and synaptic plasticity due to elevated levels of the APP intracellular domain (AICD) (41), which has been associated with the regulation of Ca 2ϩ signaling (22,38). Acute knockdown of APP in adult mouse brain in vivo impairs hippocampus-dependent spatial working memory (66).…”

mentioning

confidence: 99%

Dysregulation of Ca²⁺ signaling in astrocytes from mice lacking amyloid precursor protein

Linde

Baryshnikov

Mazzocco-Spezzia

et al. 2011

American Journal of Physiology-Cell Physiology

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The relationship between altered metabolism of the amyloid-β precursor protein (APP) and Alzheimer's disease is well established but the physiological roles of APP still remain unclear. Here, we studied Ca(2+) signaling in primary cultured and freshly dissociated cortical astrocytes from APP knockout (KO) mice and from Tg5469 mice overproducing by five- to sixfold wild-type APP. Resting cytosolic Ca(2+) (measured with fura-2) was not altered in cultured astrocytes from APP KO mice. The stored Ca(2+) evaluated by measuring peak amplitude of cyclopiazonic acid [CPA, endoplasmic reticulum (ER) Ca(2+) ATPase inhibitor]-induced Ca(2+) transients in Ca(2+)-free medium was significantly smaller in APP KO astrocytes than in wild-type cells. Store-operated Ca(2+) entry (SOCE) activated by ER Ca(2+) store depletion with CPA was also greatly reduced in APP KO astrocytes. This reflected a downregulated expression in APP KO astrocytes of TRPC1 (C-type transient receptor potential) and Orai1 proteins, essential components of store-operated channels (SOCs). Indeed, silencer RNA (siRNA) knockdown of Orai1 protein expression in wild-type astrocytes significantly attenuated SOCE. SOCE was also essentially reduced in freshly dissociated APP KO astrocytes. Importantly, knockdown of APP with siRNA in cultured wild-type astrocytes markedly attenuated ATP- and CPA-induced ER Ca(2+) release and extracellular Ca(2+) influx. The latter correlated with downregulation of TRPC1. Overproduction of APP in Tg5469 mice did not alter, however, the stored Ca(2+) level, SOCE, and expression of TRPC1/4/5 in cultured astrocytes from these mice. The data demonstrate that the functional role of APP in astrocytes involves the regulation of TRPC1/Orai1-encoded SOCs critical for Ca(2+) signaling.

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“…The ␥-cleavage releases two peptides: A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively) and an intracellular product APP intracellular domain (AID)/AICD. Several findings point to the short AID/AICD as a biologically active intracellular peptide, which may modulate cell death, Notch signaling, gene transcription, and Ca 2ϩ homeostasis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In an alternative pathway, APP is processed by ␣-secretase within the A␤ sequence, leading to the production of the soluble sAPP␣ ectodomain and a membrane-bound C-terminal fragment of 83 amino acids (C83).…”

mentioning

confidence: 99%

BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

Matsuda

D’Adamio

2009

Journal of Biological Chemistry

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Alzheimer disease (AD) is characterized by senile plaques, which are mainly composed of ␤ amyloid (A␤) peptides. A␤ is cleaved off from amyloid precursor protein (APP) with consecutive proteolytic processing: ␤-secretase, followed by ␥-secretase. Here, we show that BRI3, a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2, interacts with APP and serves as an endogenous negative regulator of A␤ production. BRI3 colocalizes with APP along neuritis in differentiated N2a cells; endogenous BRI3-APP complexes are readily detectable in mouse brain extract; reducing endogenous BRI3 levels by RNA interference results in increased A␤ secretion. BRI3 resembles BRI2, because BRI3 overexpression reduces both ␣-and ␤-APP cleavage. We propose that BRI3 inhibits the various processing of APP by blocking the access of ␣-and ␤-secretases to APP. However, unlike BRI2, the binding of BRI3 to the ␤-secretase cleaved APP C-terminal fragment is negligible and BRI3 does not cause the massive accumulation of this APP fragment, suggesting that, unlike BRI2, BRI3 is a poor ␥-cleavage inhibitor. Competitive inhibition of APP processing by BRI3 may provide a new approach to AD therapy and prevention.About 1% of humans aged 60 -64 years have AD, 2 increasing steadily to as many as 35-40% after age 85 (1). AD progressively leads to a severely impaired state and complete social dependence. At autopsy, cerebral atrophy, neurofibrillary tangles, and amyloid plaques are observed in the hippocampus, entorhinal cortex, amygdala, and other areas. Tangles consist of intraneuronal masses of helically wound filaments of the hyperphosphorylated protein, Tau. Plaques are extracellular deposits of A␤, a peptide derived from cleavage of APP, surrounded by dystrophic neurites. Most AD cases present A␤ deposits in cortical and/or meningeal microvessels. In a minority of cases, this vascular cerebral amyloid angiopathy is rather severe (2).APP is a type I transmembrane protein that undergoes a series of proteolytic cleavages (3). ␤-Secretase cleaves APP into a soluble ectodomain (sAPP␤) and a membrane-bound C-terminal fragment of 99 amino acids (C99). C99 is cleaved by the ␥-secretase, which consists of a multicomponent complex composed of presenilins (PS1 and PS2), Nicastrin, PEN2, and APH1 (4). The ␥-cleavage releases two peptides: A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively) and an intracellular product APP intracellular domain (AID)/AICD. Several findings point to the short AID/AICD as a biologically active intracellular peptide, which may modulate cell death, Notch signaling, gene transcription, and Ca 2ϩ homeostasis (5-19). In an alternative pathway, APP is processed by ␣-secretase within the A␤ sequence, leading to the production of the soluble sAPP␣ ectodomain and a membrane-bound C-terminal fragment of 83 amino acids (C83). For aged patients, a family history of dementia is a major risk factor for AD, and 10 -15% of all AD subjects have a family history c...

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Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content

Abstract: Consecutive cleavages of amyloid precursor protein (APP) generate APP intracellular domain (AICD).

Cited by 58 publications

References 47 publications

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Dysregulation of Ca²⁺ signaling in astrocytes from mice lacking amyloid precursor protein

BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

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Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content

Abstract: Consecutive cleavages of amyloid precursor protein (APP) generate APP intracellular domain (AICD).

Cited by 58 publications

References 47 publications

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein

BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

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Dysregulation of Ca²⁺ signaling in astrocytes from mice lacking amyloid precursor protein