The amyloid-β peptide and its role in Alzheimer's disease

Journal of Peptide Science

Volumn 7, Issue 5, 2001, Pages 227-249

  Clippingdale, Andrew B ^a   Wade, John D ^a   Barrow, Colin J ^a,b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b Ocean Nutrition Canada Ltd   (Canada)

Author keywords

Aggregation; Alzheimer's disease; Amyloid; Amyloid peptide; Fibrilogenesis; Metal ions; Neurotoxicity; Peptide synthesis; Structural analysis; Therapeutic strategies

Indexed keywords

3 4 TOLUOYL 2 [4' (3 DIETHYLAMINOPROPOZY) PHENYL] BENZOFURAN; ACETYLSALICYLIC ACID; ALPHA TOCOPHEROL; AMYLOID; AMYLOID BETA PROTEIN; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; BENZOFURAN DERIVATIVE; CARBAZOLE DERIVATIVE; CARVEDIOL; CELECOXIB; CONGO RED; CYCLOOXYGENASE 2 INHIBITOR; DAUNORUBICIN; GELSOLIN; INDOMETACIN; MELATONIN; MONOAMINE OXIDASE B INHIBITOR; NONSTEROID ANTIINFLAMMATORY AGENT; PREDNISONE; ROLITETRACYCLINE; SECRETORY PROTEIN; SELEGILINE; STEROID; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTHRITIS; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DISEASE COURSE; DRUG MECHANISM; GASTROINTESTINAL SYMPTOM; HUMAN; IMMUNIZATION; MOUSE; NEUROTOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN PURIFICATION; PROTEIN STRUCTURE; PROTEIN SYNTHESIS; SIDE EFFECT; TRANSGENIC MOUSE;

ALZHEIMER DISEASE; AMINO ACID SEQUENCE; AMYLOID BETA-PROTEIN; ANIMALS; CIRCULAR DICHROISM; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, BIOLOGICAL; MODELS, CHEMICAL; MOLECULAR SEQUENCE DATA; PEPTIDES; PROTEIN BINDING; PROTEIN ISOFORMS; PROTEIN STRUCTURE, SECONDARY; PROTEIN STRUCTURE, TERTIARY;

EID: 0034961205     PISSN: 10752617     EISSN: None     Source Type: Journal    
DOI: 10.1002/psc.324     Document Type: Article

References (231)

1. Proteins on the brain
2. Structural and kinetic features of amyloid Alzheimer's disease and related disorders association of New South Wales - Protein fibrilogenesis
3. Amyloid protein and Alzheimer's disease
4. The molecular pathology of Alzheimer's disease
5. A new disease of the cortex
6. The neuropathology of Alzheimer's disease: Diagnostic features and standardization
7. Amyloid plaque core protein in Alzheimer disease and down syndrome
8. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
9. Alzheimer's disease: A cell biological perspective
10. Amyloid β protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus
11. Cellular actions of β-amyloid precursor protein and its soluble and fibrilogenic derivatives
12. Differential APP gene expression in rat cerebral cortex meninges and primary astroglial, microglial and neuronal cultures
13. The alternatively spliced kunitz protease inhibitor domain alters amyloid β protein precursor processing and amyloid β protein production in cultured cells
14. Chemical characterization of Aβ 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer's Disease
15. P3 β-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain
16. The 'nonamyloidogenic' p3 fragment β amyloid (17-42) is a major constituent of Down's syndrome cerebellar preamyloid
17. Amyloidogenicity of βA4 and βA4-bearing amyloid protein precursor fragments by metalcatalyzed oxidation
18. Regulation of amyloid precursor protein cleavage
19. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPS
20. AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria
21. Mechanism of the cleavage specificity of Alzheimer's disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein
22. Amyloid β-peptide is produced by cultured cells during normal metabolism
23. Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease
24. Cleavage of Alzheimer's amyloid precursor protein by α-secretase occurs at the surface of neuronal cells
25. Caveolae, plasma membrane microdomains for α-secretase-mediated processing of the amyloid precursor protein
26. Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-Golgi network
27. Amyloid precursor protein cleavage by a membrane-bound protease
28. Alzheimer's α-secretase may be a calcium dependent protease
29. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease
30. The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-α convertase
31. Alzheimers amyloid precursor protein-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: Similarities to the angiotensin converting enzyme secretase
32. Production of the Alzheimer amyloid β protein by normal proteolytic processing
33. Late compartments of amyloid precursor protein transport in SY5Y cells are involved in β-amyloid secretion
34. Metabolism of the Swedish amyloid precursor protein variant in Neuro2A (N2A) cells - Evidence that cleavage at the β-secretase site occurs in the Golgi apparatus
35. Aβ (1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells
36. Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides
37. Cleavage of Alzheimer's amyloid precursor protein (APP) by secretases occurs after O-glycosylation of APP in the protein secretory pathway
38. Mass spectrometry of purified amyloid β protein in Alzheimer's disease
39. Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids
40. Relative abundance of Alzheimer Aβ amyloid peptide variants in Alzheimer disease and normal aging
41. Dominant and differential deposition of distinct β-amyloid peptide species. AβN3(pE), in Senile Plaques
42. The Aβ 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater β-sheet forming and aggregation propensities in vitro than full-length Aβ
43. Enzymatic generation of the amino terminus of the β-amyloid peptide
44. Membrane-anchored aspartyl proteases with Alzheimer's disease β-secretase activity
45. Identification of a novel aspartic protease (Asp 2) as β-secretase
46. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
47. Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism
48. The carboxyl termini of β-amyloid peptide 1-40 and 1-42 are generated by distinct γ-secretase activities
49. Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different protease activities
50. Candidate γ-secretases in the generation of the carboxyl terminus of the Alzheimer's disease βA4 amyloid: Possible involvement of cathepsin D
51. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
52. Two transmembrane aspartases in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity
53. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanisms of Alzheimer's disease
54. The role of presenilin-1 in the γ-secretase cleavage of the amyloid precursor protein of Alzheimer's disease
55. The transmembrane aspartates in presenilin-1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation
56. Alzheimers disease: Genotypes, phenotype, and treatments
57. Alzheimer's disease and the amyloid β-protein: What is the role of amyloid?
58. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage Dutch type
59. Amyloid β-protein precursor gene and hereditary cerebral hemorrhage with amyloidosis
60. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
61. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene
62. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production
63. Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice
64. Alzheimer-type neuropathology in transgenic mice over-expressing V717F β-amyloid precursor protein
65. Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer's disease
66. Neurotrophic and neurotoxic effects of amyloid β protein: Reversal by Tachykinin neuropeptides
67. In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity
68. Amyloid neurotoxicity requires fibril formation and is inhibited by Congo red
69. Structure-activity analyses of β-amyloid peptides: Contributions of the β25-35 region to aggregation and neurotoxicity
70. Chemical synthesis of peptides and proteins
71. Amino acid structure and 'difficult sequences' in solid phase peptide synthesis
72. Some 'difficult sequences' made easy
73. Solution structures of β peptide and its constituent fragments: Relation to amyloid deposition
74. Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer's disease
75. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the Aβ peptide of Alzheimer's disease
76. In situ neutralization in boc-chemistry solid phase peptide synthesis
77. The synthesis and spectroscopic analysis of the neurotoxic prion peptide 106-126: Comparative use of manual Boc and Fmoc chemistry
78. Synthesis, structure and neurotoxicity of the Aβ peptide of Alzheimer's disease
79. Assembly and aggregation properties of synthetic Alzheimer's A4 β amyloid peptide analogs
80. Investigation of β-amyloid peptide by on-line high performance liquid chromatography coupled to electrospray ionization mass spectrometry
81. Characterization of the minor impurities during synthesis of Alzheimer β-protein
82. Improved solid-phase synthesis of amyloid proteins associated with neurodegenerative diseases
83. Synthesis of amyloid β-peptides: Segment condensation of sparingly soluble protected peptides in chloroform-phenol mixed solvent
84. Solution synthesis of human midkine: A novel heparin-binding neurotrophic factor consisting of 121 amino acid residues with five disulphide bonds
85. Preparation and purification of β-amyloid (1-43) via soluble, amide backbone protected intermediates
86. Improved preparation of β-amyloid(1-43): Structural insights leading to optimised positioning of N-(2-Hydroxy-4-Methoxybenzyl) (Hmb) backbone amide protection
87. The synthesis of some peptides related to the amyloid β peptide 25-35: Use of N-(2-hydroxy-4-methoxybenzyl) protection
88. Conformational studies on β-amyloid protein carboxy-terminal region (residues 34-42): Strategic use of amide backbone protection as a structural probe
89. A reversible protecting group for the amide bond in peptides. Use in synthesis of 'difficult sequences'
90. Synthesis and secondary structural studies of (Hmb-Ac)5-β 1-40
91. Rapid semi-online monitoring of Fmoc solid-phase peptide synthesis by matrix-assited laser desorption ionization mass spectrometry
92. Secondary structural modifications of Aβ (1-40) induced by multiple 2-acetoxy-4-methoxybenzyl (AcetylHmb) protection
93. Synthetic peptide homologous to β protein from Alzheimer disease forms amyloid-like fibrils in vitro
94. On the nucleation and growth of amyloid-β protein fibrils: Detection of nuclei and quantitation of rate constants
95. Amyloid β-protein fibrilogenesis: Detection of a protofibrillar intermediate
96. High-resolution electron microscopic analysis of the amyloid fibril in Alzheimer's disease
97. Ultrastructural morphology of amyloid fibrils from neuritic and amyloid plaques
98. X-ray diffraction from interneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-β conformation
99. Propagating structure of Alzheimer's β-amyloid(10-35) is parallel β-sheet with residues in exact register
100. A molecular model of Alzheimer amyloid β-peptide fibril formation
101. Common core structure of amyloid fibrils by synchotron X-ray diffraction
102. An atomic model for the pleated β-sheet structure of Aβ amyloid protofilaments
103. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease
104. Surfactant properties of Alzheimer's Aβ peptides and the mechanism of amyloid aggregation
105. Observation of metastable Aβ amyloid protofibrils by atomic force microscopy
106. Assembly of amyloid protofibrils: An in vitro model for a possible early event in Alzheimer's disease
107. Amyloid β-protein fibrillogenesis: Structure and biological activity of protofibrillar intermediates
108. Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons
109. In situ atomic force microscopy study of Alzheimer's β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation
110. Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-β protein
111. Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous β-sheet helix
112. Analysis of X-ray diffraction patterns from amyloid of biopsied vitreous humor and kidney of transthyretin (TTR) Met30 familial amyloidotic polyneuropathy (FAP) patients - Axially arrayed TTR monomers constitute amyloid
113. Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease
114. Protein misfolding, evolution and disease
115. Designing conditions for in vitro formation of amyloid protofilaments and fibrils
116. NMR studies of amyloid β-peptides: Proton assignments, secondary structure, and mechanism of an α-helix to β-sheet conversion for a homologous, 28-residue, N-terminal fragment
117. Residue specific pKa measurements of the β-peptide and mechanism of ph-induced amyloid formation
118. Tests of the helix dipole model for stabilization of α-helices
119. Influence of glycine residues on peptide conformation in membrane environments
120. Peptide environment specifies conformation
121. Solution structure of amyloid β-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?
122. Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease
123. Three-dimensional structures of the amyloid β peptide (25-35) in Membrane-Mimicking Environment
124. Circular dichroism and optical rotary dispersion of proteins and polypeptides
125. Computed circular dichroism spectra for the evaluation of protein conformation
126. Circular dichroic analysis of protein conformation: Inclusion of the β-turns
127. Interaction of an apolipoprotein (ApoLP-Alanine) with phosphatidylcholine
128. A set of constructed type spectra for the practical estimation of peptide secondary structure from circular dichroism
129. Solution structures of β peptide and its constituent fragments: Relation to amyloid deposition
130. Effect of trifluoroethanol on protein secondary structure: An NMR and CD study using a synthetic actin peptide
131. Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer's disease
132. Human and rodent Alzheimer β-amyloid peptides acquire distinct conformations in membrane-mimicking solvents
133. Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias
134. Isolation, chemical characterization, and quantitation of Aβ 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits
135. Lactam bridge stabilization of α-helices: The role of hydrophobicity in controlling dimeric versus monomeric α-helices
136. Neuritic plaque amyloid in Alzheimer's disease is highly racemized
137. Structural alterations in the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer's disease
138. Full-length amyloid-β (1-42(43)) and amino terminally modified and truncated amyloid-(42(43) deposits in diffuse plaques
139. Irreversible dimerization tetramerization and post-translational modifications inhibit proteolytic degradation of Aβ peptides of Alzheimer's disease
140. Synthetic post-translationally modified human Aβ peptide exhibits a markedly increased tendency to form β-pleated sheets in vitro
141. The effects of aspartic acid-bond isomerization on in vitro properties of the amyloid β-peptide as modelled with N-terminal decapeptide fragments
142. Assembly and aggregation properties of synthetic Alzheimer's A4 β amyloid peptide analogs
143. Aggregation of Aβ Alzheimer's disease-related peptide studied by dynamic light scattering
144. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease
145. Interaction between Aβ (1-42) and Aβ (1-40) in Alzheimer's β-amyloid fibril formation in vitro
146. Trace elements in Alzheimer's disease
147. Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis
148. Experimental production of neurofibrillary degeneration I. Light microscope observations
149. Selective accumulation of aluminium and iron in the neurofibrillary tangles of Alzheimer's disease: A laser microprobe (LAMMA) study
150. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide
151. Copper, iron and zinc in Alzheimer's disease senile plaques
152. A novel zinc(II) binding site modulates the function of the βA4 amyloid protein precursor of Alzheimer's disease
153. Rapid induction of Alzheimer Aβ amyloid formation by zinc
154. Zinc-induced aggregation of human and rat β-amyloid peptides in vitro
155. Zinc-induced Alzheimer's Aβ1-40 aggregation is mediated by conformational factors
156. Selective aggregation of endogenous β-amyloid peptide and soluble amyloid precursor protein in cerebrospinal fluid by zinc
157. Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by biometal depletion
158. Modulation of Aβ adhesiveness and secretase site cleavage by zinc
159. Alzheimer's disease amyloidogenic glycoprotein: Expression pattern in rat brain suggests a role in cell contact
160. Conservation of the sequence of the Alzheimer's disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis
161. Histidine- 13 is a crucial residue in the zinc ion-induced aggregation of the Aβ peptide of Alzheimer's disease
162. Self-aggregation of Alzheimer's Aβ is induced by attomolar affinity copper binding
163. Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion
164. Cell surface extensions associated with over-expression of Alzheimer β/A4 amyloid
165. Membrane surface ruffling in cells that over-express Alzheimer amyloid β/A4 C-terminal peptide
166. Giant multilevel cation channels formed by Alzheimer disease amyloid β-protein [AP-(1-40)] in bilayer membranes
167. Alzheimer disease amyloid β protein forms calcium channels in bilayer membranes: Blockade by tromethamine and aluminum
168. 2+-sensitive channel in reconstituted lipid vesicles
169. 2+ channel activity by β-amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons
170. Membrane alterations and causes of impaired signal transduction in Alzheimer's disease and aging
171. 2+ interaction with Alzheimer amyloid β protein calcium channels
172. Membrane disruption by Alzheimer β-amyloid peptides mediated through specific binding to either phospholipids or gangliosides
173. Structural transitions associated with the interaction of Alzheimer β-amyloid peptides with gangliosides
174. Interactions of Alzheimer amyloid-β peptides with glycosaminoglycans: Effects on fibril nucleation and growth
175. Interactions of amyloid β-peptide (1-40) with ganglioside-containing membranes
176. Structure of the Alzheimer β-amyloid peptide (25-35) and its interaction with negatively charged phospholipid vesicles
177. Lipid binding to amyloid β-peptide aggregates: Preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids
178. Caspase-12 mediates endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid-β
179. Caspase-2 mediates neuronal cell death induced by β-amyloid
180. Alzheimer's disease and inflammation: A review of cellular and therapeutic mechanisms
181. Amyloid-β and amyloid fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia
182. Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer's amyloid β-peptide by microglial cells
183. The lipid peroxidation product, 4-Hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins
184. 2+ homeostasis in Alzheimer's disease
185. Amyloid β-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells
186. Central role of oxyradicals in the mechanism of amyloid β-peptide cytotoxicity
187. A role for 4-hydroxynonenal, and aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β peptide
188. 2+ channels: A possible involvement of free radicals
189. β amyloid-mediated vasoactivity and vascular endothelial damage
190. Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: Relevance to Alzheimer's disease
191. Amyloid protein enhances macrophage production of oxygen free radicals and glutamate
192. Is Alzheimer's a disease of oxidative stress?
193. Oxidative stress and mitochondrial dysfunction in neurodegeneration
194. Hydrogen peroxide mediates amyloid β protein toxicity
195. Amyloid β-peptide stimulated nitric oxide production in astrocytes through an NFκB-dependent mechanism
196. 2 radical forming NADPH oxidase in microglia, monocytes and neutrophils
197. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
198. Amyloid-β binds catalase with high affinity and inhibits hydrogen peroxide breakdown
199. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
200. Amyloid ox-tox transducers
201. Iron accumulation in Alzheimer disease is a source of redoxgenerated free radicals
202. The Aβ peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction
203. Cu(II) potentiation of Alzheimer Aβ neurotoxicity
204. Free radicals and lipid peroxidation do not mediate β-amyloid-induced neuronal cell death
205. Treatment of Alzheimer's disease
206. Parkinson's disease
207. Neuroprotection by S-Nitrosoglutathione of brain dopamine neurons from oxidative stress
208. Searching for drugs that combat Alzheimer's
209. Supplementary benefits?
210. Presinilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease
211. Oxidative damage and cell death induced by an amyloid peptide fragment is completely prevented by melatonin
212. Charge-based binding of complement component C1q to the Alzheimer amyloid β-peptide
213. Gelsolin inhibits the fibrillization of amyloid (-protein, and also defibrillizes its preformed fibrils
214. Inhibition of Alzheimer's amyloidosis by peptides that prevent β-sheet conformation
215. Inhibition of Alzheimer's amyloidogenesis by anti-β-sheet peptides
216. β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy
217. Controlling polymerization of β-amyloid and prion-derived peptides with synthetic small molecule ligands
218. A short synthesis of the β-amyloid aggregation inhibitor 3-p-Toluoyl-2-[4′-(3-diethylaminopropoxy)-phenyl]-benzofuran
219. Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation
220. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
221. Antibody clears senile plaques
222. Inhibitors of β-amyloid formation based on the β-secretase cleavage site
223. Enzymes point way to potential Alzheimer's therapies