title: Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid.
abstract: Since Alois Alzheimer first described morphological alterations associated with his patient's dementia more than 100 years ago, Alzheimer's disease (AD) was defined as neurodegenerative disease caused by extracellular deposits of misfolded proteins. These amyloid plaques and neurofibrillary tangles have been unambiguously considered as hallmarks of this ailment, accompanied by devastating brain atrophy and cell loss. When a 40-42 amino acid peptide, called beta-amyloid (Abeta), was identified as a main component of amyloid plaques and a few genetic cases of AD were linked to Abeta metabolism, the Abeta hypothesis of AD was proposed. It was initially thought that an increase in Abeta42 precipitates plaque formation, which causes the generation of neurofibrillary tangles and ultimately the death of neurons. However, during the last decade it became apparent that soluble rather than deposited Abeta is associated with dementia. Among the constituents of soluble Abeta, small oligomeric forms were increasingly associated with neuropathology. There is now ample evidence that Abeta oligomers do not affect neuronal viability in general, but interfere specifically with synaptic function. Long-term neurophysiological impairment ultimately causes degeneration of synapses, which becomes most apparent on the morphological level by retraction of dendritic spines. Loss of meaningful synaptic connections in the brain of patients with AD will shatter their capacity to encode and retrieve memories. The precise molecular mechanism of Abeta oligomer-induced impairment of synaptic transmission is not fully understood, but there are several independent observations that oligomers interfere with the vesicular release machinery at the presynaptic terminal. While this hypothesis offers a promising avenue to understand the underlying cause of cognition and memory deficits in the AD brain, it also opens a possibility to address new mechanisms for preventing and ultimately curing AD.
authors.affiliation: Neuroscience Discovery, GPRD, Abbott, Ludwigshafen, Germany. volker.nimmrich@abbott.com
authors.forename: Volker
authors.initials: V
authors.lastname: Nimmrich
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ebert
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D010446:Peptide Fragments