Genetic alterations of the BRI2 gene: familial British and Danish dementias.
Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.
Ghiso
J
J
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. ghisoj01@popmail.med.nyu.edu
Rostagno
A
A
Tomidokoro
Y
Y
Lashley
T
T
Bojsen-Møller
M
M
Braendgaard
H
H
Plant
G
G
Holton
J
J
Lal
R
R
Revesz
T
T
Frangione
B
B
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000473:pathology; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D003718:Denmark; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D006113:United Kingdom
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins