Secretase targets for Alzheimer's disease: Identification and therapeutic potential

Journal of Medicinal Chemistry

Volumn 44, Issue 13, 2001, Pages 2039-2060

  Wolfe, M S ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; BETA SECRETASE; BETA SECRETASE INHIBITOR; MEMBRANE PROTEIN; NOOTROPIC AGENT; NOTCH RECEPTOR; PRESENILIN 1; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; DRUG TARGETING; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME SPECIFICITY; GENE MUTATION; GENETIC POLYMORPHISM; MOUSE; NONHUMAN; PROTEIN DEGRADATION; PROTEIN PROCESSING; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; AMINO ACID SEQUENCE; AMYLOID; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ENDOPEPTIDASES; ENDOPEPTIDASES; HUMANS; ISOENZYMES; MOLECULAR SEQUENCE DATA;

EID: 0035927426     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0004897     Document Type: Review

References (214)

1. Aberrant protein deposition and neurological disease
2. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
3. The association between quantitative measure of dementia and of senile change in the cerebral grey matter of elderly subjects
4. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia
5. Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity
6. Activation of microglial cells by beta-amyloid protein and interferon-gamma
7. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils
8. Association of microglia with amyloid plaques in brains of APP23 transgenic mice
9. Microglial activation in early stages of amyloid beta protein deposition
10. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain
11. Alzheimer's disease: Genotypes, phenotypes, and treatments
12. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene
13. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
14. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease
15. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production
16. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor
17. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants
18. Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor
19. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation
20. Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease
21. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells transgenic mice
22. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 APP mutations linked to familial Alzheimer's disease
23. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): I - A review of clinical, radiologic and genetic aspects
24. Presence of soluble amyloid betapeptide precedes amyloid plaque formation in Down's syndrome
25. The AMY antigen co-occurs with abeta and follows its deposition in the amyloid plaques of Alzheimer's disease and down syndrome
26. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
27. Candidate gene for the chromosome 1 familial Alzheimer's disease locus
28. The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue
29. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1
30. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
31. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
32. APOE genotype predicts when-not whether-one is predisposed to develop Alzheimer disease
33. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease
34. Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
35. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease
36. Translating cell biology into therapeutic advances in Alzheimer's disease
37. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation implications for the pathogenesis of Alzheimer's disease
38. Neurodegeneration induced by beta-amyloid peptides in vitro: The role of peptide assembly state
39. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red
40. Genetic dissection of Alzheimer's disease and related dementias: Amyloid and its relationship to tau
41. Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome
42. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: A regional quantitative analysis
43. Intraneuronal Abeta42 accumulation in human brain
44. Risk of Alzheimer's disease and duration of NSAID use
45. A strategy for designing inhibitors of beta toxicity
46. Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger
47. Selective inhibition of Abeta fibril formation
48. Disaggregation ofAlzheimer beta-amyloid by site-directed mAb
49. Alzheimer's disease. A firm base for drug development
50. Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer's amyloid protein precursor
51. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease
52. In search of gamma-secretase: Presenilin at the cutting edge
53. Amyloid beta-peptide is produced by cultured cells during normal metabolism
54. Production of the Alzheimer amyloid beta protein by normal proteolytic processing
55. Isolation quantification of soluble Alzheimer's betapeptide from biological fluids
56. Generation ofbeta-amyloid in the secretory pathway in neuronal and nonneuronal cells
57. Assisted protein folding
58. Molecular chaperones in cellular protein folding
59. The proteasome, a novel protease regulated by multiple mechanisms
60. The secretory pathway: Mechanisms of protein sorting and transport
61. Trafficking of lysosomal enzymes
62. Post-Golgi biosynthetic trafficking
63. Intracellular transport of GPI-anchored proteins
64. Membrane protein secretases
65. Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease
66. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide
67. Betasecretase processing of the beta-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes
68. Evidence that production and release of amyloid beta-protein involves the endocytic pathway
69. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42
70. Presenilin 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in endoplasmic reticulum and Golgi
71. Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42
72. Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells
73. Novel beta-secretase cleavage of beta-amyloid precursor protein in the endoplasmic reticulum/intermediate compartment of NT2N cells
74. The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway
75. Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides
76. Generation of amyloid beta protein from its precursor is sequence specific
77. beta-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
78. Purification and cloning of amyloid precursor protein beta-secretase from human brain
79. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity
80. Identification of a Novel Aspartic Protease (Asp 2) as beta-Secretase
81. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein
82. Functional analysis of beta-secretase using mutagenesis and structural homology modeling
83. Maturation and endosomal targeting of BACE: The Alzheimer's disease beta-Secretase
84. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's-secretase
85. Characterization of Alzheimer's beta-secretase protein BACE. A pepsin family member with unusual properties
86. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease β-secretase
87. BACE maps to chromosome 11 and a BACE homolog, BACE2, resides in the obligate Down syndrome region of chromosome 21
88. BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein
89. Design of potent inhibitors for human brain memapsin 2 (beta-secretase)
90. Mode of inhibition of acid proteases by pepstatin
91. Renin inhibitors
92. Design of tight-binding human immunodeficiency virus type 1 protease inhibitors
93. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor
94. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein
95. Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice
96. HIV protease: A novel chemotherapeutic target for AIDS
97. An essential role for ectodomain shedding in mammalian development
98. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons
99. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation
100. beta-Amyloid formation as a potential therapeutic target for Alzheimer's disease
101. Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions
102. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene
103. Amyloid, the presenilins and Alzheimer's disease
104. Earlyonset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum
105. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm
106. Skeletal and CNS defects in Presenilin-l-deficient mice
107. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
108. Mice lacking both presenilin genes exhibit early embryonic patterning defects
109. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency
110. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells
111. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1
112. Inhibition of betaamyloid formation identifies proteolytic precursors and subcellular site of catabolism
113. The carboxyl termini of beta-amyloid peptides 1-40 and 1-42 are generated by distinct gamma-secretase activities
114. Two crystal structures of the leupeptin-trypsin complex
115. Highly potent and specific inhibitors of human renin
116. Peptide aldehydes as inhibitors of HIV protease
117. Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities
118. A combinatorial approach to the identification of dipeptide aldehyde inhibitors ofbeta-amyloid production
119. A substrate-based difluoro ketone selectively inhibits Alzheimer's γ-secretase activity
120. Design and synthesis of potent and specific renin inhibitors containing difluorostatine, difluorostatone, and related analogues
121. Direct observation by X-ray analysis of the tetrahedral "intermediate" of aspartic proteinases
122. Crystallographic analysis of transition state mimics bound to penicillopepsin: Difiuorostatine- and difluorostatine-containing peptides
123. Inhibition and catalytic mechanism of HIV-1 aspartic protease
124. Inhibition of chymotrypsin by fluorinated alpha-keto acid derivatives
125. Peptidomimetic probes molecular modeling suggest Alzheimer's γ-secretases are intramembrane-cleaving aspartyl proteases
126. Calpain inhibitor I increases beta-amyloid peptide production by inhibiting the degradation of the substrate of gamma-secretase. Evidence that substrate availability limits beta-amyloid peptide production
127. Rank-order of potencies for inhibition of the secretion of abeta40 and abeta42 suggests that both are generated by a single gamma-secretase
128. Beta-amyloid precursor protein. Location of transmembrane domain and specificity of gamma-secretase cleavage
129. Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43)
130. Mutations in the transmembrane domain of APP altering gamma-secretase specificity
131. Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein
132. Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors
133. Difluoro Ketone peptidomimetics suggest a Large S1 pocket for Alzheimer's γ-secretase: Implications for inhibitor design
134. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease
135. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor
136. Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment
137. Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning
138. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs
139. Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins
140. Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease
141. Protein topology of presenilin 1
142. Membrane topology of the C. elegans SEL-12 presenilin
143. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins
144. Evidence for a sixtransmembrane domain structure of presenilin 1
145. The seven-transmembrane spanning topography of the Alzheimer disease-related presenilin proteins in the plasma membranes of cultured cells
146. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo
147. The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150 kDa molecular mass complex
148. Endoproteolytic processing and stabilization of wild-type and mutant presenilin
149. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue
150. Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation
151. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors
152. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans
153. The biological and pathological function of the presenilin-1 Aexon 9 mutation is independent of its defect to undergo proteolytic processing
154. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abetal-42/1-40 ratio in vitro and in vivo
155. Subcellular distribution and turnover of presenilins in transfected cells
156. Mutation of conserved aspartates affect maturation of both aspartate-mutant and endogenous presenilin 1 and presenilin 2 complexes
157. Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana
158. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity
159. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis
160. Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis
161. The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid Β-protein generation
162. A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling
163. Notch signaling: Cell fate control and signal integration in development
164. The Notch1 receptor is cleaved constitutively by a furin-like convertase
165. Novel proteolytic cleavage involved in notch signaling: The role of the disintegrin-metalloprotease TACE
166. Ligand-induced extracellular cleavage regulates secretase-like proteoiytic proteolytic activation of Notch1
167. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain
168. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1
169. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
170. Aspartate mutations in presenilin and g-secretase inhibitors both impair Notch1 proteolysis and nuclear translocation with relative preservation of Notch1 signaling
171. Cell surface presenilin-1 participates in the γ-secretase-like proteolysis of Notch
172. Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch
173. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos
174. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abetal-42/43 expression
175. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations
176. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing
177. Separation of presenilin function in amyloid beta-peptide generation endoproteolysis
178. Presenilin 1 controls gammasecretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons
179. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: Alternative processing into amyloid-bearing fragments
180. Interaction between amyloid precursor protein and presenilins in mammalian cells: Implications for the pathogenesis of Alzheimer disease
181. Formation of stable complexes between two Alzheimer's disease gene products: Presenilin-2 and beta-amyloid precursor protein
182. Evidence for a physical interaction between presenilin and Notch
183. Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta -protein generation
184. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins
185. Presenilin 1 is linked with gamma -secretase activity in the detergent solubilized state
186. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity
187. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1
188. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1
189. Presenilin-1 and 2 are molecular targets for gamma secretase inhibitors
190. Fenchylamine sulfonamide inhibitors of amyloid beta peptide production by the gamma-secretase proteolytic pathway: Potential small-molecule therapeutic agents for the treatment of Alzheimer's disease
191. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain
192. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein
193. Cleavage of amyloid beta peptide during constitutive processing of its precursor
194. Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion
195. Effects of the amyloid precursor protein Glu693 → Gln 'Dutch' mutation on the production and stability of amyloid beta-protein
196. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type
197. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch)
198. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the betaamyloid precursor protein gene
199. Beta-amyloid precursor protein cleavage by a membrane-bound protease
200. Activation of protein kinase C inhibits cellular production of the amyloid betaprotein
201. Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide
202. Reversal of the Swedish familial Alzheimer's disease mutant phenotype in cultured cells treated with phorbol 12,13-dibutyrate
203. The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment
204. Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors
205. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors
206. Amyloid precursor protein secretion via muscarinic receptors reduced desensitization using the M1-selective agonist AF102B
207. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells
208. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation
209. Alzheimer's amyloid precursor protein alpha-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: Similarities to the angiotensin converting enzyme secretase
210. The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-alpha convertase
211. SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling