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	Field	Term

General Information:

Id:	792
Diseases:	Alzheimer disease - [OMIM]
Organism:	Mammalia
Publication type:	review
Reference:	Koren J 3rd et al.(2009) Chaperone signalling complexes in Alzheimers disease J. Cell. Mol. Med. 13: 619-630 [PMID: 19449461]

Interaction Information:

Comment	Polymorphisms in the APOE (apolipoprotein E) gene have been identified as significant risk factors for late-onset AD (LOAD).
Formal Description Interaction-ID: 4542	gene/protein mutant APOE-mut increases_activity of disease Alzheimer disease

Comment	The mutations in APOE linked to LOAD reduce the efficiency with which ApoE clears the Abeta peptide, facilitating amyloid accumulation and disease progression.
Formal Description Interaction-ID: 4543	gene/protein mutant APOE-mut affects_quantity of gene/protein Amyloid beta peptide

Comment	Genetic analyses of families presenting with Alzheimer dementia revealed that mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) protein were the cause of the disease for the affected kindred.
Formal Description Interaction-ID: 4544	gene/protein mutant APP-mut increases_activity of disease Alzheimer disease

Comment	Genetic analyses of families presenting with Alzheimer dementia revealed that mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) protein were the cause of the disease for the affected kindred.
Formal Description Interaction-ID: 4545	gene/protein mutant PSEN1-mut increases_activity of disease Alzheimer disease

Comment	Overexpression of PSEN1 and APP mutant genes in transgenic mice showed that they enhance production of a 42-amino acid N-terminal peptide from APP, which enters the extracellular milieu (amyloidosis).
Formal Description Interaction-ID: 4546	gene/protein mutant APP-mut increases_processing of gene/protein Amyloid beta peptide (42) in extracellular milieu; if APP-mut is overexpressed

Comment	Overexpression of PSEN1 and APP mutant genes in transgenic mice showed that they enhance production of a 42-amino acid N-terminal peptide from APP, which enters the extracellular milieu (amyloidosis).
Formal Description Interaction-ID: 4547	gene/protein mutant PSEN1-mut increases_processing of gene/protein Amyloid beta peptide (42) in extracellular milieu; if PSEN1-mut is overexpressed

Comment	Abeta peptide has amyloidogenic properties, forming multimers in a beta-sheet structure. As enough of this material is produced, amyloid plaques form spontaneously and remain quite stable over time. Amyloidosis around the vasculature is also found in Alzheimer's disease (AD), and these plaques have been shown to grow more gradually with time.
Formal Description Interaction-ID: 4548	gene/protein Amyloid beta peptide affects_activity of phenotype amyloidosis

Comment	Abeta peptide has amyloidogenic properties, forming multimers in a beta-sheet structure. As enough of this material is produced, amyloid plaques form spontaneously and remain quite stable over time. Amyloidosis around the vasculature is also found in Alzheimer's disease (AD), and these plaques have been shown to grow more gradually with time.
Formal Description Interaction-ID: 4551	gene/protein Amyloid beta peptide affects_quantity of phenotype amyloid beta deposits

Comment	Amyloid beta deposits are formation of self-assembled aggregates of the cleaved amyloid beta peptides (e.g. 42), one of the main hallmarks of AD.
Formal Description Interaction-ID: 4553	disease Alzheimer disease increases_quantity of phenotype amyloid beta deposits

Comment	Amyloidosis around the vasculature is also found in Alzheimer disease (AD).
Formal Description Interaction-ID: 4554	disease Alzheimer disease increases_activity of phenotype amyloidosis

Comment	Plaque production facilitates gliosis.
Formal Description Interaction-ID: 4573	phenotype amyloid beta deposits increases_activity of phenotype gliosis

Comment	CHIP, carboxy-terminus of Hsc70-interacting protein, is a TPR-containing chaperone and a highly conserved ubiquitin ligase that is critical for quality control and stress recovery systems, and binds with both Hsp70 and Hsp90.
Formal Description Interaction-ID: 4605	gene/protein STUB1 interacts (colocalizes) with gene/protein HSP70

Comment	CHIP, carboxy-terminus of Hsc70-interacting protein, is a TPR-containing chaperone and a highly conserved ubiquitin ligase that is critical for quality control and stress recovery systems, and binds with both Hsp70 and Hsp90.
Formal Description Interaction-ID: 4606	gene/protein STUB1 interacts (colocalizes) with gene/protein HSP90

Comment	Hsp90 normally inhibits HSF1 by tethering it to the cytosol, preventing it from translocating to the nucleus.
Formal Description Interaction-ID: 4608	gene/protein HSP90 decreases_activity of gene/protein HSF1

Comment	Once HSF1 becomes phosphorylated, it trimerises and is able to enter the nucleus and begin transcribing genes containing heat shock elements (HSE), such as Hsp70 and Hsp27.
Formal Description Interaction-ID: 4609	protein modification HSF1-phos affects_expression of gene/protein HSP70 in nucleus

Comment	Once HSF1 becomes phosphorylated, it trimerises and is able to enter the nucleus and begin transcribing genes containing heat shock elements (HSE), such as Hsp70 and Hsp27.
Formal Description Interaction-ID: 4611	protein modification HSF1-phos affects_expression of gene/protein HSPB1 in nucleus

Comment	Hsp27 and Hsp70, were elevated in affected regions from AD brain tissue. This elevation appears to be a hybridisation of activated glia and dysregulated/stressed neurons.
Formal Description Interaction-ID: 4613	disease Alzheimer disease increases_quantity of gene/protein HSPB1

Comment	Hsp27 and Hsp70, were elevated in affected regions from AD brain tissue. This elevation appears to be a hybridisation of activated glia and dysregulated/stressed neurons.
Formal Description Interaction-ID: 4614	disease Alzheimer disease increases_quantity of gene/protein HSP70

Comment	The ER chaperone BiP/Grp78 (the ER isoform of Hsp70) associates with APP, likely indicating that Grp94 (the ER isoform of Hsp90) can regulate APP as well.
Formal Description Interaction-ID: 4623	gene/protein HSPA5 interacts (colocalizes) with gene/protein APP in endoplasmic reticulum
Drugbank entries	Show/Hide entries for HSPA5 or APP
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB02235	Methionine Sulfoxide not specified APP
Drugbank DB02235	Methionine Sulfoxide not specified APP

Comment	The ER chaperone BiP/Grp78 (the ER isoform of Hsp70) associates with APP, likely indicating that Grp94 (the ER isoform of Hsp90) can regulate APP as well.
Formal Description Interaction-ID: 4626	gene/protein HSPA5 is localized in cellular component endoplasmic reticulum
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	CHIP also interacts with APP.
Formal Description Interaction-ID: 4628	gene/protein STUB1 interacts (colocalizes) with gene/protein APP
Drugbank entries	Show/Hide entries for APP
Drugbank DB02235	Methionine Sulfoxide not specified APP
Drugbank DB02235	Methionine Sulfoxide not specified APP

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 4635	gene/protein HSPB8 interacts (colocalizes) with phenotype amyloid beta deposits

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 4678	gene/protein HSPB8 decreases_quantity of phenotype amyloid beta deposits

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 4679	gene/protein HSPB1 interacts (colocalizes) with phenotype amyloid beta deposits

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 4680	gene/protein HSPB1 decreases_quantity of phenotype amyloid beta deposits

Comment	HSF1 induces the APP gene during stress.
Formal Description Interaction-ID: 4681	gene/protein HSF1 increases_expression of gene/protein APP during stress
Drugbank entries	Show/Hide entries for APP
Drugbank DB02235	Methionine Sulfoxide not specified APP
Drugbank DB02235	Methionine Sulfoxide not specified APP

Comment	PS1 forms aggresomes within the ER upon heat shock stress. The functional consequence of these aggresomes remains unclear.
Formal Description Interaction-ID: 4682	gene/protein PSEN1 increases_activity of process aggresome assembly in endoplasmic reticulum; as response to heat shock stress (GO:0009408 )

Comment	Hsp27, HSP70 and CHIP, can recognise abnormal tau and reduce its concentration by facilitating its degradation and dephosphorylation.
Formal Description Interaction-ID: 4683	gene/protein HSPB1 decreases_quantity of protein modification MAPT-hyperphos

Comment	Hsp27 preferentially binds to hyperphosphorylated tau as well as paired helical filamentous tau but not to non-phosphorylated tau.
Formal Description Interaction-ID: 4684	gene/protein HSPB1 interacts (colocalizes) with protein modification MAPT-hyperphos

Comment	Hsp27 preferentially binds to hyperphosphorylated tau as well as paired helical filamentous tau but not to non-phosphorylated tau.
Formal Description Interaction-ID: 4685	gene/protein HSPB1 NOT interacts (colocalizes) with gene/protein MAPT

Comment	Hsp27 preferentially binds to hyperphosphorylated tau as well as paired helical filamentous tau but not to non-phosphorylated tau.
Formal Description Interaction-ID: 4686	gene/protein HSPB1 interacts (colocalizes) with phenotype tau protein deposits

Comment	Hsp27 increases tau phosphorylation at Ser262.
Formal Description Interaction-ID: 4687	gene/protein HSPB1 increases_phosphorylation of gene/protein MAPT at Ser262

Comment	AlphaB-crystallin decreases phosphorylated tau and GSK-3beta levels.
Formal Description Interaction-ID: 4688	gene/protein CRYAB decreases_quantity of protein modification MAPT-phos

Comment	AlphaB-crystallin decreases phosphorylated tau and GSK-3beta levels.
Formal Description Interaction-ID: 4689	gene/protein CRYAB decreases_quantity of protein modification GSK3B-phos

Comment	Tau binds directly to Hsp70.
Formal Description Interaction-ID: 4690	gene/protein MAPT interacts (colocalizes) with gene/protein HSP70

Comment	Pharmacologic inhibition of Hsp90 significantly reduced intracellular levels of the disease-associated phosphorylated tau species pS202/T205 and pS396/S404. These Hsp90 inhibitors primarily facilitated the clearance of phospho-tau via proteasomal degradation.
Formal Description Interaction-ID: 4691	gene/protein HSP90 affects_quantity of protein modification MAPT-phosSer202Thr205

Comment	Pharmacologic inhibition of Hsp90 significantly reduced intracellular levels of the disease-associated phosphorylated tau species pS202/T205 and pS396/S404. These Hsp90 inhibitors primarily facilitated the clearance of phospho-tau via proteasomal degradation.
Formal Description Interaction-ID: 4692	gene/protein HSP90 affects_quantity of protein modification MAPT-phosSer396Ser404

Comment	Akt, an oncogenic master kinase that can phosphorylate tau, is also elevated in AD.
Formal Description Interaction-ID: 4693	disease Alzheimer disease increases_quantity of gene/protein AKT1
Drugbank entries	Show/Hide entries for AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01169	Arsenic trioxide inducer AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1
Drugbank DB07584	N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phe ... not specified AKT1
Drugbank DB07585	5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4 ... not specified AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1

Comment	Akt can regulate CHIP expression levels.
Formal Description Interaction-ID: 4695	gene/protein AKT1 affects_expression of gene/protein STUB1
Drugbank entries	Show/Hide entries for AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01169	Arsenic trioxide inducer AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1
Drugbank DB07584	N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phe ... not specified AKT1
Drugbank DB07585	5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4 ... not specified AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1

Comment	Akt enhances the activity of PAR1, to promote phosphorylation of tau at S262/S356, a phospho-tau species that is not recognised by the Hsp90/CHIP complex.
Formal Description Interaction-ID: 4696	gene/protein AKT1 increases_activity of gene/protein MARK2
Drugbank entries	Show/Hide entries for AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01169	Arsenic trioxide inducer AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1
Drugbank DB07584	N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phe ... not specified AKT1
Drugbank DB07585	5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4 ... not specified AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1

Comment	Akt, an oncogenic master kinase that can phosphorylate tau, is also elevated in AD.
Formal Description Interaction-ID: 4697	gene/protein AKT1 affects_phosphorylation of gene/protein MAPT
Drugbank entries	Show/Hide entries for AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01169	Arsenic trioxide inducer AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1
Drugbank DB07584	N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phe ... not specified AKT1
Drugbank DB07585	5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4 ... not specified AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1

Comment	Hsp27, HSP70 and CHIP, can recognise abnormal tau and reduce its concentration by facilitating its degradation and dephosphorylation.
Formal Description Interaction-ID: 23595	gene/protein HSP70 decreases_quantity of protein modification MAPT-hyperphos

Comment	Hsp27, HSP70 and CHIP, can recognise abnormal tau and reduce its concentration by facilitating its degradation and dephosphorylation.
Formal Description Interaction-ID: 23596	gene/protein STUB1 decreases_quantity of protein modification MAPT-hyperphos

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 80153	gene/protein HSPB8 decreases_activity of process amyloid fibril formation

Comment	Small Hsps such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and actually inhibit their fibrillarisation.
Formal Description Interaction-ID: 80154	gene/protein HSPB1 decreases_activity of process amyloid fibril formation

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