Alzheimer's disease - Homo sapiens (human)

Curator(s): Joe Strothman

Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.    
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Alzheimer's disease - Homo sapiens (human) cluster_OutNeuron OutNeuron cluster_Membrane Membrane cluster_node41 !n cluster_ER ER cluster_Mitochondria Mitochondria cluster_node42 !out Microglia node8 IL-1 Microglia->node8 tumor necrosis factor TNF Microglia->TNF node1 3 node2 3 node6 21 node7 3 node12 6 node14 2 node20 8 node23 2 node24 2 node25 9 caspase 9,apoptosis-related cysteine peptidase CASP9 CASP9->node25 CASP9 node26 26 node27 15 node29 3 node30 1 node31 5 node32 1 node33 5 node34 26 node35 5 Cell death node40 7 node40->Cell death node36 (Tau-P)n node37 Paired helical filaments (PHFs) node36->node37 node38 Neurofibrillary tangles (NFTs) node37->node38 node9 1 Neuronal injury node9->Neuronal injury node16 2 AICD node16->AICD Amyloid beta node16->Amyloid beta Induction of apoptosis AICD->Induction of apoptosis Modulation of gene expression AICD->Modulation of gene expression insulin-degrading enzyme IDE Amyloid beta->IDE node3 LPL APOE Amyloid beta->node3 NEP Amyloid beta->NEP Oligomeric intracellular Abeta Amyloid beta->Oligomeric intracellular Abeta OligomericAbeta Amyloid beta->OligomericAbeta node17 3 C99 node17->C99 sAAbeta node17->sAAbeta C99->node16 node18 4 C83 node18->C83 sAAalpha node18->sAAalpha node22 5 CytC node22->CytC CytC->node24 CytC CytC->CASP9 node39 6 node39->Cell death ABAD ATP depletion ABAD->ATP depletion Fall in mitocondrial membrane potential ABAD->Fall in mitocondrial membrane potential Increased ROS ABAD->Increased ROS ATP depletion->node40 Fall in mitocondrial membrane potential->node40 Increased ROS->node40 ADAM ADAM->node18 Modulation of gene expression->Cell death apoptotic peptidase activating factor 1 APAF1 APAF1->CASP9 amyloid beta (A4) precursor protein APP APP->node1 APP APP->node17 APP->node18 node13 APP-BP1 APP->node13 Fe65 APP->Fe65 GAPD APP->GAPD Apoptosis 1 node13->Apoptosis 1 APP processing Fe65->APP processing node19 Decreased energy production? GAPD->node19 Abeta glycogen synthase kinase 3 beta GSK3B Abeta->GSK3B GSK3B->node33 GSK3B Tau GSK3B->Tau +p node10 Aggr. amyloid node11 Ca2+ node10->node11 node21 Ca2+ Overload node11->node21 CaM node11->CaM Calpain node11->Calpain node28 ERK1/2 node11->node28 NOS node11->NOS SERCA node11->SERCA Degradation IDE->Degradation LRP node3->LRP NEP->Degradation Oligomeric intracellular Abeta->ABAD Cx IV Oligomeric intracellular Abeta->Cx IV OligomericAbeta->node10 H2O2 OligomericAbeta->H2O2 FasTNFR OligomericAbeta->FasTNFR GPCR OligomericAbeta->GPCR Senile plaques OligomericAbeta->Senile plaques NMDAR OligomericAbeta->NMDAR VDCC OligomericAbeta->VDCC Apoptosis Apoptosis->node39 BACE BACE->node14 BACE BACE->node17 BCL2-associated agonist of cell death BAD BAD->node23 BAD BAD->node22 BH3 interacting domain death agonist BID BID->node22 caspase 12 (gene/pseudogene) CASP12 caspase 3,apoptosis-related cysteine peptidase CASP3 CASP12->CASP3 CASP3->node26 CASP3 CASP3->Cell death CASP3 2 CASP3 2->node34 CASP3 2 CASP3 2->Tau Tau->node32 Tau Tau->node36 caspase 7,apoptosis-related cysteine peptidase CASP7 CASP7->node35 CASP7 CASP7->CASP3 2 caspase 8,apoptosis-related cysteine peptidase CASP8 CASP8->node12 CASP8 CASP8->BID CASP8->CASP3 cyclin-dependent kinase 5 CDK5 CDK5->Tau +p Cn CaM->Cn Calpain->node30 Calpain node28->node27 ERK1/2 node28->CASP3 NOS->node31 NOS NO NOS->NO ER Stress SERCA->ER Stress Cn->BAD -p node4 Cu+ node4->H2O2 H2O2->node9 Cx IV->node20 Cx IV Cx IV 2 Cx IV->Cx IV 2 Cx IV 2->ATP depletion Cx IV 2->Fall in mitocondrial membrane potential Cx IV 2->Increased ROS DNA Damage DNA Damage->node39 ER Stress->CASP12 Fas (TNFRSF6)-associated via death domain FADD FADD->CASP8 FasTNFR->node2 FasTNFR FasTNFR->FADD node5 Fe2+ node5->H2O2 Gq GPCR->Gq PLC Gq->PLC IP3 PLC->IP3 node8->node7 IL-1 node8->node9 IP3R IP3->IP3R IP3R->node11 Inflammation Inflammation->node39 Abeta aggregation LRP->Abeta aggregation TNF->node6 TNF TNF->node9 Mitochondrial dysfunction 2 Mitochondrial dysfunction 2->node39 NAC NAC->Senile plaques Senile plaques->Microglia NMDAR->node11 ONOO NO->ONOO ONOO->Apoptosis ONOO->DNA Damage ONOO->Inflammation ONOO->Mitochondrial dysfunction 2 Lipid peroxidation ONOO->Lipid peroxidation Protein oxidation ONOO->Protein oxidation node38->Cell death Protein oxidation->node39 VDCC->node11 PSEN PSEN->node29 PSEN PSEN->node11 activating transcription factor 6 ATF6 PSEN->ATF6 IRE1alpha PSEN->IRE1alpha PERK PSEN->PERK RyR PSEN->RyR RyR->node11 node15 PSENEN PSEN1 PSEN2 NCSTN APH1A node15->node16 synuclein,alpha (non A4 component of amyloid precursor) SNCA SNCA->NAC Fragmentation p25 p25->Tau +p p35 p35->p25 Cx I Mitochondrial dysfunction print "