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CNS Neuroprotection pp 409–422Cite as

Neurohormonal Signalling Pathways and the Regulation of Alzheimer β-Amyloid Metabolism Integrating Basic and Clinical Observations for Developing Successful Strategies to Delay, Retard or Prevent Cerebral Amyloidosis in Alzheimer’s Disease

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 155))

Abstract

Alzheimer’s disease (AD) is characterized by the intracranial accumulation of the 4-kDa amyloid-β peptide (Aβ), following proteolysis of a ∼ 700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to Alzheimer’s disease has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial Alzheimer’s disease (FAD). Though FAD is rare (<10% of all AD), the hallmark features — amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits, dementia — are indistinguishable when FAD is compared with typical, common, “non-familial,” or sporadic, AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to enhanced generation or aggregability of Aβ, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of Aβ.

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  1. Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Frank W. Marcoux (Vice President, Biology) (Vice President, Biology)

  2. Department of Neurology Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Dennis W. Choi

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Gandy, S. (2002). Neurohormonal Signalling Pathways and the Regulation of Alzheimer β-Amyloid Metabolism Integrating Basic and Clinical Observations for Developing Successful Strategies to Delay, Retard or Prevent Cerebral Amyloidosis in Alzheimer’s Disease. In: Marcoux, F.W., Choi, D.W. (eds) CNS Neuroprotection. Handbook of Experimental Pharmacology, vol 155. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-06274-6_15

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