Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease

Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Zimmermann, Martina [verfasserIn] Gardoni, Fabrizio Di Luca, Monica

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2005

Schlagwörter:	Memantine Amyloid Precursor Protein Senile Plaque Amyloid Precursor Protein Processing Amyloid Precursor Protein Metabolism

Anmerkung:	© Adis Data Information BV 2005

Übergeordnetes Werk:	Enthalten in: Drugs & aging - Berlin [u.a.] : Springer, 1991, 22(2005), Suppl 1 vom: Dez., Seite 27-37
Übergeordnetes Werk:	volume:22 ; year:2005 ; number:Suppl 1 ; month:12 ; pages:27-37

Links:	Volltext

DOI / URN:	10.2165/00002512-200522001-00003

Katalog-ID:	SPR033237603

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allfields	10.2165/00002512-200522001-00003 doi (DE-627)SPR033237603 (SPR)00002512-200522001-00003-e DE-627 ger DE-627 rakwb eng Zimmermann, Martina verfasserin aut Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease 2005 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Adis Data Information BV 2005 Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213 Gardoni, Fabrizio aut Di Luca, Monica aut Enthalten in Drugs & aging Berlin [u.a.] : Springer, 1991 22(2005), Suppl 1 vom: Dez., Seite 27-37 (DE-627)327644281 (DE-600)2043689-0 1179-1969 nnns volume:22 year:2005 number:Suppl 1 month:12 pages:27-37 https://dx.doi.org/10.2165/00002512-200522001-00003 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 22 2005 Suppl 1 12 27-37
spelling	10.2165/00002512-200522001-00003 doi (DE-627)SPR033237603 (SPR)00002512-200522001-00003-e DE-627 ger DE-627 rakwb eng Zimmermann, Martina verfasserin aut Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease 2005 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Adis Data Information BV 2005 Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213 Gardoni, Fabrizio aut Di Luca, Monica aut Enthalten in Drugs & aging Berlin [u.a.] : Springer, 1991 22(2005), Suppl 1 vom: Dez., Seite 27-37 (DE-627)327644281 (DE-600)2043689-0 1179-1969 nnns volume:22 year:2005 number:Suppl 1 month:12 pages:27-37 https://dx.doi.org/10.2165/00002512-200522001-00003 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 22 2005 Suppl 1 12 27-37
allfields_unstemmed	10.2165/00002512-200522001-00003 doi (DE-627)SPR033237603 (SPR)00002512-200522001-00003-e DE-627 ger DE-627 rakwb eng Zimmermann, Martina verfasserin aut Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease 2005 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Adis Data Information BV 2005 Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213 Gardoni, Fabrizio aut Di Luca, Monica aut Enthalten in Drugs & aging Berlin [u.a.] : Springer, 1991 22(2005), Suppl 1 vom: Dez., Seite 27-37 (DE-627)327644281 (DE-600)2043689-0 1179-1969 nnns volume:22 year:2005 number:Suppl 1 month:12 pages:27-37 https://dx.doi.org/10.2165/00002512-200522001-00003 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 22 2005 Suppl 1 12 27-37
allfieldsGer	10.2165/00002512-200522001-00003 doi (DE-627)SPR033237603 (SPR)00002512-200522001-00003-e DE-627 ger DE-627 rakwb eng Zimmermann, Martina verfasserin aut Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease 2005 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Adis Data Information BV 2005 Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213 Gardoni, Fabrizio aut Di Luca, Monica aut Enthalten in Drugs & aging Berlin [u.a.] : Springer, 1991 22(2005), Suppl 1 vom: Dez., Seite 27-37 (DE-627)327644281 (DE-600)2043689-0 1179-1969 nnns volume:22 year:2005 number:Suppl 1 month:12 pages:27-37 https://dx.doi.org/10.2165/00002512-200522001-00003 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 22 2005 Suppl 1 12 27-37
allfieldsSound	10.2165/00002512-200522001-00003 doi (DE-627)SPR033237603 (SPR)00002512-200522001-00003-e DE-627 ger DE-627 rakwb eng Zimmermann, Martina verfasserin aut Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease 2005 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Adis Data Information BV 2005 Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213 Gardoni, Fabrizio aut Di Luca, Monica aut Enthalten in Drugs & aging Berlin [u.a.] : Springer, 1991 22(2005), Suppl 1 vom: Dez., Seite 27-37 (DE-627)327644281 (DE-600)2043689-0 1179-1969 nnns volume:22 year:2005 number:Suppl 1 month:12 pages:27-37 https://dx.doi.org/10.2165/00002512-200522001-00003 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 22 2005 Suppl 1 12 27-37
language	English
source	Enthalten in Drugs & aging 22(2005), Suppl 1 vom: Dez., Seite 27-37 volume:22 year:2005 number:Suppl 1 month:12 pages:27-37
sourceStr	Enthalten in Drugs & aging 22(2005), Suppl 1 vom: Dez., Seite 27-37 volume:22 year:2005 number:Suppl 1 month:12 pages:27-37
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Memantine Amyloid Precursor Protein Senile Plaque Amyloid Precursor Protein Processing Amyloid Precursor Protein Metabolism
isfreeaccess_bool	false
container_title	Drugs & aging
authorswithroles_txt_mv	Zimmermann, Martina @@aut@@ Gardoni, Fabrizio @@aut@@ Di Luca, Monica @@aut@@
publishDateDaySort_date	2005-12-01T00:00:00Z
hierarchy_top_id	327644281
id	SPR033237603
language_de	englisch
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author	Zimmermann, Martina
spellingShingle	Zimmermann, Martina misc Memantine misc Amyloid Precursor Protein misc Senile Plaque misc Amyloid Precursor Protein Processing misc Amyloid Precursor Protein Metabolism Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease
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topic_title	Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease Memantine (dpeaa)DE-He213 Amyloid Precursor Protein (dpeaa)DE-He213 Senile Plaque (dpeaa)DE-He213 Amyloid Precursor Protein Processing (dpeaa)DE-He213 Amyloid Precursor Protein Metabolism (dpeaa)DE-He213
topic	misc Memantine misc Amyloid Precursor Protein misc Senile Plaque misc Amyloid Precursor Protein Processing misc Amyloid Precursor Protein Metabolism
topic_unstemmed	misc Memantine misc Amyloid Precursor Protein misc Senile Plaque misc Amyloid Precursor Protein Processing misc Amyloid Precursor Protein Metabolism
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title	Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease
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title_full	Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease
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author_browse	Zimmermann, Martina Gardoni, Fabrizio Di Luca, Monica
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title_sort	molecular rationale for the pharmacological treatment of alzheimer’s disease
title_auth	Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease
abstract	Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. © Adis Data Information BV 2005
abstractGer	Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. © Adis Data Information BV 2005
abstract_unstemmed	Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Aβ directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway. © Adis Data Information BV 2005
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title_short	Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR033237603</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520012006.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2005 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.2165/00002512-200522001-00003</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR033237603</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)00002512-200522001-00003-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Zimmermann, Martina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2005</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Adis Data Information BV 2005</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Cerebral deposition of amyloid plaques containing amyloid β-peptide (Aβ) has traditionally been considered the central feature of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: α-, β- and γ-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of α-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-d-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-d-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated α-secretase and they reduced Aβ generation and amyloid accumulation in a transgenic mouse model. β-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for β-secretase inhibitors. γ-Secretase is not an easy candidate for pharmacological manipulation. 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Molecular Rationale for the Pharmacological Treatment of Alzheimer’s Disease

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