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Pharmacological Mechanisms in Alzheimer's Therapeutics

:	A. Claudio Cuello
:	Claudio Cuello
:	Pharmacological Mechanisms in Alzheimer's Therapeutics
:	Springer-Verlag
:	9780387715223
:	1
:	CHF 132.60
:

:	Pharmazie
:	English

:	324
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

The need for effective therapy to treat Alzheimer's disease is greater than ever, but there is still no drug therapy that can stop or reverse the progression of the disease. There is, however, a great deal of anticipation over the imminent development of effective therapies as a result of the identification of promising targets for drug development. This book investigates these targets and examines ongoing strategies to develop effective therapies for this devastating neurodegenerative condition.

	Forewords	5
	Preface from the Editor	8
	Contents	10
	List of Contributors	13
	Overview of the AlzheimerÌs Disease Pathology and Potential Therapeutic Targets	19
	Introduction	19
	Alois AlzheimerÌs Realization of a Dementia Accompanied with a Defined Brain Pathology	19
	Key Molecules in the AlzheimerÌs Pathology	21
	The Amyloid Hypothesis	22
	Tau Pathology in AlzheimerÌs	24
	Additional Components of the AlzheimerÌs Pathology	25
	Clinical Evolution and Diagnosis of AlzheimerÌs Disease, a Synopsis	27
	Genetic and Nongenetic Risk Factors in AD	28
	Nongenetic Risk Factors	29
	Aging as a Risk Factor	29
	High Plasma Cholesterol	30
	Hypertension	30
	Oxidative Stress as a Risk Factor	31
	Education, Physical Activity, and Brain Trauma and the Onset of AlzheimerÌs	31
	Synapses, Neurotransmitters, and Growth Factors in the AlzheimerÌs Pathology	32
	Present and Future Pharmacological Treatment of AlzheimerÌs Disease	34
	Concluding Remarks	38
	References	38
	Trial Designs and Outcomes to Monitor Novel Therapeutics in Alzheimer's Disease	46
	Introduction	46
	Symptomatic Treatment Versus Disease Stabilization	46
	Natural History of AlzheimerÌs Disease	47
	Symptomatic Clinical Trials Using ChEI and Memantine	49
	Disease-Modification Studies	50
	Conclusions	51
	References	51
	The Pharmacological Treatment of AlzheimerÌs Disease with Cholinesterase Inhibitors and Memantine	54
	Introduction	54
	Cholinesterase Inhibitors Tacrine	54
	Second Generation Cholinesterase Inhibitors for Mild- to- Moderate AD	55
	Cholinesterase Inhibitors in Severe AD	57
	Cholinesterase Inhibitors for the Management of Noncognitive Symptoms in Dementia	58
	Long-Term Use of Cholinesterase Inhibitors	58
	Use of Cholinesterase inhibitors in Other Conditions	60
	Memantine for the Treatment of Dementia Introduction	62
	Memantine for the Treatment of AlzheimerÌs Disease	62
	Memantine for the Treatment of Vascular Dementia	63
	Memantine Combined with a Cholinesterase Inhibitor	63
	Conclusions	64
	References	64
	M1 Muscarinic Agonists: A Comprehensive Therapy Against Major Hallmarks of Alzheimer's Disease	68
	Introduction	68
	M1 Muscarinic Agonists in AD Ò the Rationale	69
	Past Experience and Present Status	69
	Modulation of Ab Levels via M1 mAChR	70
	M1 mAChR Mediate Dephosphorylation of Tau Proteins	73
	Prevention of Ab Neurotoxic Effects	Wnt Signaling
	Relevant Clinical Data on Disease Modification	74
	Conclusions and Outlook	74
	References	76
	Cholinergic Neurodegeneration in Alzheimer's Disease:	82
	Introduction	82
	Basal Forebrain Cholinergic Neurons Anatomy	84
	Cholinergic Biochemistry and Cellular Physiology	84
	Network Physiology and Function	86
	Lesions and Cognition	88
	AlzheimerÌs Disease	89
	Animal Models of AlzheimerÌs Disease	91
	Cholinergic Neurotransmission and APP Metabolism	92
	Role of Neurotrophins in the Maintenance of BFCNs Structure and Function	93
	Failed NGF Signaling in AlzheimerÌs Disease	94
	NGF Signaling in Mouse Models of Alzheimer Overexpressing Mutant APP	95
	Mouse Models of AlzheimerÌs Disease Overexpressing Wild- Type Human APP	97
	Mouse Models of Down Syndrome	98
	Mechanisms by Which NGF Transport is Interrupted in Degenerating Cholinergic Neurons	102
	Therapeutic Strategies for AlzheimerÌs Disease Focused on Enhancing NGF Signaling	104
	Direct NGF Administration	104
	Enhancing NGF Downstream Signaling	105
	Increasing NGF Retrograde Transport	107
	Conclusions	108
	References	109
	The Rationale for Glutamatergic Therapy in Alzheimer's Disease	123
	Glutamatergic Neurotransmission	123
	Markers of Glutamate Neurotransmission in AlzheimerÌs Disease	124
	The Glutamatergic System and AD Pathology	125
	Glutamatergic System in Transgenic Models of AD	126
	Glutamatergic Approaches to Treatment of AD	126
	Conclusions	127
	References	127
	Secretases as Pharmacological Targets in Alzheimer's Disease	131
	Introduction	131
	Inhibition of ß- Secretase	133
	Inhibition of .- Secretase	135
	Activation of a- Secretase	135
	Conclusions	136
	References	137
	y-Secretase as a Target forAlzheimerÌs Disease	143
	.- Secretase and Production of Amyloid ß- Peptide	143
	Identification of the .- Secretase Complex	144
	Mechanism of .- Secretase and Role in Notch Signaling	146
	Therapeutic Potential of .- Secretase Inhibitors	148
	Therapeutic Potential of .- Secretase Modulators	150
	Conclusions	153
	References	153
	The Rationale for an Immunological Approach to Alzheimer's Therapeutics	159
	References	164
	Neuroinflammation, Alzheimer Disease, and Other Aging Disorders	167
	Introduction	167
	Microglia	168
	Mitosis	169
	Chemotaxis	169
	Phagocytosis	171
	Complement	172
	Neurotoxicity	172
	Healing	174
	Possible Use of Antiinflammatory Agents in Treating Alzheimer Disease	174
	Inflammation as an Important Factor in Many Aging Diseases	176
	References	177
	Nonsteroidal Anti-inflammatory Drugs ( NSAIDs) and Derived A 42- Lowering Molecules for Treatment and Prevention of AlzheimerÌs Disease ( AD)	185
	Prevalence, Neuropathology, and Etiology of AlzheimerÌs Disease	186
	NSAIDs and AD: The Epidemiological Evidence and Overview of Potential Mechanisms of Action	187
	Role of Inflammation in AD	188
	Protective Mechanisms Related to the Anti-inflammatory Properties of NSAIDs	191
	A 42 as a Therapeutic Target in AlzheimerÌs Disease	194
	Selective Modulation of A 42 Production with NSAIDs	195
	Clinical Trials with NSAIDs and Derived A 42- Lowering Com