Faculty Bibliography

Cerebral amyloid-beta (Abeta) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Abeta related toxicity being linked to its beta-sheet conformation and/or aggregation. We show that a beta-sheet breaker peptide (iAbeta5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAbeta5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Abeta and reduced the extent of interleukin-1beta positive microglia-like cells that surround the Abeta deposits. These findings suggest that beta-sheet breakers, such as iAbeta5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Abeta-related histopathology

Amyloidosis is a disorder of protein conformation leading to aggregation. The term defines a diverse group of proteins normally present in body fluids as soluble precursors that can be deposited as insoluble amyloid fibrils in different tissues producing organ dysfunction and cell death. These fibrils are composed of self-assembled, low molecular weight mass peptides adopting beta-pleated sheet structure, the conformation responsible for their physicochemical properties and tinctoreal characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils (Westermark et al., 1999). Collectively, they are products of normal genes; however, several amyloid precursors contain abnormal amino acid substitutions that can impose an unusual potential for self-aggregation. The molecular mass of the amyloid peptides is within the 4 to 30-kDa range, with heterogeneity at the amino- and carboxyl-terminal portions found in most amyloid proteins. Increased levels of amyloid precursors, either in the circulation or locally in sites of deposition, are usually the result of overexpression or defective clearance, or both. Of the 20 amyloid proteins identified, few of them are known to cause amyloid deposition in the central nervous system, which in turn results in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination of them

Familial British dementia (FBD) is a disorder characterized by the presence of amyloid deposits in cerebral blood vessels and brain parenchyma coexisting with neurofibrillary tangles in limbic areas. The amyloid subunit (ABri) is a 4 kDa fragment of a 266 amino acid type II single-spanning transmembrane precursor protein encoded by the BRI gene located on chromosome 13. In FBD patients, a single base substitution at the stop codon of this gene generates a larger 277-residue precursor (ABriPP-277). Proteolytic processing by a furin-like enzyme at the C-terminus of the elongated precursor generates the 34 amino acid ABri that undergoes rapid aggregation and fibrillization. ABri is structually unrelated to all known amyloids including A beta, the main component of the amyloid lesions in Alzheimer's disease (AD), indicating that cerebral deposition of amyloid molecules other than A beta can trigger similar neuropathological changes leading to neuronal loss and dementia. These data support the concept that amyloid deposition in the vascular wall and brain parenchyma is of primary importance in the initiation of neurogeneration

Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder clinically characterized by progressive dementia, spastic tetraparesis and cerebellar ataxia, with an age of onset in the fourth decade. The neuropathology of FBD (amyloid angiopathy, parenchymal plaques and neurofibrillary tangles) is similar to that of AD. Amyloid deposits in cerebral blood vessels and parenchymal plaques are mainly composed of a 4 kDa subunit, ^ABri, derived from a type II transmembrane precursor molecule mutated at the stop codon. The mutation produces a longer open reading frame that generates a larger 277 aa precursor. ^ABri is a 34 amino acids peptide released by proteolytic processing of the C-terminus of the mutated precursor protein (ABriPP277). We have identified soluble ABri (sABri) in serum and CSF of patients with FBD using a combination of immunoprecipitation, mass spectrometry and western blot analysis. The 4 kDa component was present in all tested carriers of the Stop-to-Arg mutation and consistently absent in non-carrier family members and normal controls. In contrast to the CNS-deposited ^ABri, sABri was monomeric and devoided of N-terminal pyroglutamate. In view of these findings, we tested systemic organs in an autopsy case of FBD for amyloid deposits. Antibodies specific to the ^ABri peptide labeled Congo red positive vascular lesions in several peripheral organs; in addition, parenchymal immunoreactivity was also seen in many of the tissues tested. Biochemical analysis of the deposited material isolated from pancreas, uterus and skeletal muscle identified ^ABri species similar to those found in amyloid lesions in the CNS (Nature, 399:776,1999). The main component was full-length ABri featuring N-terminus pyroglutamate. The data indicate that amyloid formation in FBD occurs not only in the brain but also peripherally. This is the first case of cerebral amyloidosis associated with neurodegeneration in demented patients where the amyloid deposition is also systemic

This review summarizes recent advancements in our understanding of the potential role of the amyloid beta protein in Alzheimer's disease. It also discusses the significance of amyloid beta in initiating the generation of partially reduced oxygen species and points out their role in damaging essential macromolecules in the CNS which leads to neuronal dysfunction and loss. Recently acquired experimental data links these destructive oxidative processes with some neurodegenerative aspects of Alzheimer's disease. The experimental findings related to the free radical scavenging and antioxidative properties of melatonin are tabulated and its efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reactive species in experimental models of Alzheimer's disease are summarized. Besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from its antiamyloidogenic properties. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier