Disease relevance of App

• In this study, we carried out gene silencing analysis by means of RNA interference with synthetic small interfering RNA duplexes targeting the App, Aplp1 and Aplp2 genes in Neuro2a (N2a) cells, a mouse neuroblastoma cell line [1].
• Here we demonstrate that neuronal overexpression of the epsilon isozyme of PKC decreases Abeta levels, plaque burden, and plaque-associated neuritic dystrophy and reactive astrocytosis in transgenic mice expressing familial AD-mutant forms of the human amyloid precursor protein (APP) [2].
• We have examined transgenic mouse models (PS1M146L, APPK670N,M671L) and a doubly transgenic line (APPK670N,M671L + PS1M146L) that overexpress mutated AD-related genes [presenilin-1 (PS1) and the amyloid precursor protein (APP)] to investigate the effect of AD-related gene overexpression and/or amyloidosis on cholinergic parameters [3].
• Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis [4].
• Transgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the beta-amyloid as senile plaques and cerebral amyloid angiopathy [5].
• The triple transgenic animals (moAPP x APPswe/PS1dE9) produced 20% more A beta but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings [6].

Psychiatry related information on App

• Cerebral deposition of beta-amyloid (Abeta) peptides is an invariant pathological hallmark in brains of patients with Alzheimer's disease (AD) and transgenic mice coexpressing familial AD-linked APP and PS1 variants [7].
• Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS [8].
• Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans [4].
• Limited proteolysis enhanced immunostaining of amyloid plaques in human brain sections from patients with CJD or GSS [9].
• These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias [10].

High impact information on App

• The enzymatic activity of an Abeta-degrading endopeptidase, neprilysin, is elevated in the brains of "enriched" mice and inversely correlated with amyloid burden [7].
• These studies provide evidence that environmental enrichment leads to reductions in steady-state levels of cerebral Abeta peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice [7].
• Islet amyloid and type 2 diabetes mellitus [11].
• Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo [12].
• The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice [13].

Chemical compound and disease context of App

• Estrogen alters amyloid precursor protein as well as dendritic and cholinergic markers in a mouse model of Down syndrome [14].
• Increased production of neurotoxic forms of amyloid beta-peptide (Abeta) and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD) [15].
• The efficacy of STI571 in reducing Abeta without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease [16].
• By unveiling a link between homocysteine and Abeta levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD [17].
• Expression of the genes encoding the beta/A4 amyloid protein precursor (APP) and microtubule-associated protein tau was studied in an embryonal carcinoma cell line (P19) that differentiates in vitro into cholinergic neurons after treatment with retinoic acid [18].

Biological context of App

• The results demonstrated that cell viability and neurite outgrowth of N2a cells undergoing knockdown of Aplp1 were significantly reduced, compared with N2a cells undergoing knockdown of either App or Aplp2 [1].
• Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, Abeta sequestration, and prostaglandin synthesis [7].
• The fast anterograde axonal transport of this compartment is mediated by APP and kinesin-I [19].
• Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the "gamma-secretase" cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide [20].
• The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-beta precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS [8].

Anatomical context of App

• Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates [21].
• Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease [22].
• The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques [23].
• We have previously shown that the axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain subunit of kinesin-I, a microtubule motor protein [19].
• In contrast, almost no gamma-secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif [24].

Associations of App with chemical compounds

• The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP [22].
• Conversely, inhibition of PLD1 activity by 1-butanol decreases betaAPP trafficking in both wt and PS1-deficient cells [25].
• Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro [4].
• Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein [26].
• Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and beta Amyloid in Mouse Microglia Cells [27].

Physical interactions of App

• Together, these results establish that nicastrin is an essential component of the multimeric gamma-secretase complex in mammals required for both gamma-secretase activity and APP trafficking and suggest that nicastrin may be a valuable therapeutic target for Alzheimer's disease [28].
• However, the precise individual roles of the three cofactors in the PS complex in Abeta generation remain to be clarified [29].
• Glypican bound strongly to the APP affinity column [30].
• Recently we found that AChE forms complexes with the Abeta peptide in vitro and that these are more cytotoxic than Abeta fibrils alone [31].
• beta-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a membrane-bound aspartic protease that cleaves amyloid precursor protein to produce a neurotoxic peptide, Abeta, and is implicated in triggering the pathogenesis of Alzheimer disease [32].

Enzymatic interactions of App

• Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain [33].
• The amyloid beta-protein precursor (APP) is proteolytically cleaved to generate the amyloid beta-protein (Abeta), the principal constituent of senile plaques found in Alzheimer's disease (AD) [34].
• Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the beta-secretase site [35].
• In vivo, the levels of soluble amyloid beta protein correlated with caspase-cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects [36].
• An increase in the phosphorylation of microtubule-associated protein MAP-1B, which accompanies neurite outgrowth induced by serum deprivation, is also observed upon addition of the two antiprotease synthetic peptides, although the nexin-2 (amyloid) peptide induces a less marked increase in phosphorylated MAP-1B than does the nexin-1 peptide [37].

Co-localisations of App

• We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta [38].

Regulatory relationships of App

• Overexpression of PLD1 in PS1wt cells promotes generation of betaAPP-containing vesicles from the trans-Golgi network [25].
• These observations clearly indicate that X11L suppresses the amyloidogenic but not amyloidolytic processing of APP in regions of the brain such as the hippocampus, which express significant levels of X11L [39].
• Neprilysin regulates amyloid Beta peptide levels [40].
• Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant amyloid precursor protein (APP) relative to age-matched wild-type mice [15].
• These results suggest that endogenously overproduced Abeta induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation [41].

Other interactions of App

• Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP [19].
• Surface delivery of betaAPP is also increased by PLD1 in these cells [25].
• PS, a critical component of gamma-secretase, is responsible for the intramembranous cleavage of amyloid precursor protein and Notch [42].
• IFN-gamma signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age [43].
• Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides. Inability of truncated forms of PS2 with familial Alzheimer's disease mutation to increase secretion of Abeta42 [44].

Analytical, diagnostic and therapeutic context of App

• An early specific cell-cell interaction occurs in the production of beta-amyloid in cell cultures [45].
• Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice [46].
• However, the causal link between Abeta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD [47].
• Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry [48].
• A homogeneous time-resolved fluorescence immunoassay for detection of beta-amyloid (A beta) peptides has been adapted for quantification of A beta(40) and A beta(42) accumulation in brains of APP695SWE transgenic mice [49].

References