A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP

Leissring, Malcolm A.; Murphy, Michael P.; Mead, Tonya R.; Akbari, Yama; Sugarman, Michael C.; Jannatipour, Mehrdad; Anliker, Brigitte; Müller, Ulrike; Säftig, Paul; Strooper, Bart De; Wolfe, Michael S.; Golde, Todd E.; LaFerla, Frank M.

doi:10.1073/pnas.072033799

Cited by 254 publications

(212 citation statements)

References 31 publications

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“…Under these conditions we did not observe differential regulation of previously described AICD target genes such as KAI1 (Table 2). We could not detect regulation of other putative target genes, including SERCA2B (Leissring et al, 2002) or GSK3␤ (Kim et al, 2003). However, our data are in agreement with other groups who could not detect AICD-dependent regulation of these genes in AICD/FE65 transgenic mice (Ryan and Pimplikar, 2005) or in cell lines with pharmacological inhibition or deficiency of ␥-secretase activity (Hebert et al, 2006).…”

Section: Discussionsupporting

confidence: 79%

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Müller

Concannon

Ward

et al. 2007

MBoC

123

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Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of ␤-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD).Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including ␣2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system. INTRODUCTIONThe amyloid precursor protein (APP) is a type-1 transmembrane protein composed of a large extracellular and a small intracellular domain and has been widely implicated in the pathogenesis of Alzheimer's disease (AD). APP can undergo proteolytic cleavage by ␤-and ␥-secretase activities, resulting in the production of ␤-amyloid (A␤) (Selkoe, 1994). A␤ is the main constituent of amyloid plaques and is thought to be neurotoxic by inducing oxidative stress, inflammation, and neurodegeneration (Mattson, 2004). The intraneuronal accumulation of A␤ protofibrils is thought to cause progressive neurotoxicity in cortical neurons (Hartley et al., 1999). In addition, the secretion of soluble A␤ oligomers inhibits hippocampal long-term potentiation and alters the memory of complex learned behavior (Walsh et al., 2005).The APP intracellular domain (AICD), a small 6-kDa protein, originates from APP cleavage mediated by ␥-secretase activity (Octave et al., 2000). This cleavage can occur after Val636 (AICD59), Ala638 (AICD57), or Leu645 (AICD50) corresponding to the ␥-or -cleavage site ( Figure 1A) of the ␥-secretase complex (Sastre et al., 2001;Yu et al., 2001). More recently, AICD was shown to have transactivation potential (Cao and Sudhof, 2001). AICD levels are detectable in membrane fractions of murine total brain homogenates, and they increase significantly in mice overexpressing the Swedish mutation of human APP (Ryan and Pimplikar, 2005). Moreover, Hirano bodies found in the degenerating neurons of Alzheimer's patients stain positive with antisera raised against the cytoplasmic domain of APP (Munoz et al., 1993), suggesting an accumulation of AICD during Alzheimer...

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Section: Discussionsupporting

confidence: 79%

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Müller

Concannon

Ward

et al. 2007

MBoC

123

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“…The 99 amino acid C-terminal fragment of APP generated by BACE cleavage can be internalized and further processed by γ-secretase to produce Aβ40/42 in endocytic compartments. Cleavage of C99 by γ-secretase liberates an APP intracellular domain (AICD) that can translocate to the nucleus where it may regulate gene expression including the induction of apoptotic genes 66 . Cleavage of APP/C99 by caspases produces a neurotoxic peptide (C31) 67 .…”

Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,784

2,058

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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“…However, reports on the molecular mechanism that underlies presenilin FAD-dependent Ca 2ϩ dyshomeostasis have been inconclusive and often contradictory. It has been suggested that changes in ␥-secretase-mediated production of the AICD are responsible for aberrant Ca 2ϩ signaling observed in cells expressing FAD mutant presenilin (42). However, Herms and colleagues (43) have demonstrated that CCE deficits associated with FAD mutant presenilins occur even in the absence of APP (and AICD).…”

Section: Discussionmentioning

confidence: 99%

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

Landman

Jeong

Shin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

121

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Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid ␤-peptide (A␤42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A␤42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.␤-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry

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A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP

Cited by 254 publications

References 31 publications

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Pathways towards and away from Alzheimer's disease

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

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