Natural oligomers of the amyloid-β protein specifically disrupt cognitive function

A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-β protein interferes with cognitive function. Soluble oligomeric forms of amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.

[1]  R. Katzman.,et al.  Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques , 1988, Annals of neurology.

[2]  C. Duyckaerts,et al.  Large amounts of neocortical βA4 deposits without neuritic plaques nor tangles in a psychometrically assessed, non-demented person , 1990, Neuroscience Letters.

[3]  J. Hardy,et al.  Amyloid deposition as the central event in the aetiology of Alzheimer's disease. , 1991, Trends in pharmacological sciences.

[4]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[5]  J. Price,et al.  The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease , 1991, Neurobiology of Aging.

[6]  C. Cotman,et al.  Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. , 1991, European journal of pharmacology.

[7]  B. Yankner,et al.  Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Overmier,et al.  Effects of an exogenous β-amyloid peptide on retention for spatial learning , 1994 .

[9]  J Carter,et al.  Molecular Pathology of Alzheimer's Disease , 2013 .

[10]  W. Honer,et al.  Correlations of synaptic and pathological markers with cognition of the elderly , 1995, Neurobiology of Aging.

[11]  P. Mantyh,et al.  Beta-amyloid(1–40) effects on behavior and memory , 1995, Brain Research.

[12]  Brian J Cummings,et al.  Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity , 1995, The Lancet.

[13]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[14]  J. Cleary,et al.  Utilization of a novel model of food reinforced behavior involving neuropeptide Y, insulin, 2-deoxy-d-glucose and naloxone. , 1996, Behavioural pharmacology.

[15]  Expression in brain of amyloid precursor protein mutated in the alpha‐secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. , 1996 .

[16]  J. Cleary,et al.  Alternating lever cyclic-ratio schedule analysis of the effects of atropine sulfate , 1996, Pharmacology Biochemistry and Behavior.

[17]  B. Strooper,et al.  801 Expression in brain of Amyloid Precursor Protein mutated in the α-secretase site, causes disturbed behavior, neuronal degeneration and premature death in transgenic mice , 1996, Neurobiology of Aging.

[18]  J. Overmier,et al.  Intrahippocampal Injections of Exogenous β-Amyloid Induce Postdelay Errors in an Eight-Arm Radial Maze , 1997, Neurobiology of Learning and Memory.

[19]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[20]  B. Hyman,et al.  APPSW Transgenic Mice Develop Age‐related Aβ Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1 , 1997, Journal of neuropathology and experimental neurology.

[21]  B. Hyman,et al.  Aβ Deposition Is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse , 1997, The Journal of Neuroscience.

[22]  Bruce A. Yankner,et al.  Aging renders the brain vulnerable to amyloid β-protein neurotoxicity , 1998, Nature Medicine.

[23]  P. Mantyh,et al.  Delayed behavioral effects following intrahippocampal injection of aggregated Aβ(1–42) , 1999, Brain Research.

[24]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Masters,et al.  Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease , 1999, Annals of neurology.

[26]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[28]  D. Selkoe,et al.  The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. , 2000, Biochemistry.

[29]  K. Abe,et al.  The scopolamine-induced impairment of spatial cognition parallels the acetylcholine release in the ventral hippocampus in rats. , 2000, Japanese journal of pharmacology.

[30]  Guiquan Chen,et al.  A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease , 2000, Nature.

[31]  K. Davis,et al.  Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. , 2000, JAMA.

[32]  J. Bureš,et al.  Specific spatial learning deficits become severe with age in β-amyloid precursor protein transgenic mice that harbor diffuse β-amyloid deposits but do not form plaques , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Harding,et al.  A role for the angiotensin AT4 receptor subtype in overcoming scopolamine-induced spatial memory deficits , 2001, Regulatory Peptides.

[34]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[35]  G. M. Cole,et al.  Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology , 2001, Neurobiology of Aging.

[36]  Brett Chromy,et al.  Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus , 2002, Brain Research.

[37]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[38]  Yadin Dudai,et al.  Memory from A to Z: Keywords, Concepts, and Beyond , 2002 .

[39]  R. L. Richardson,et al.  Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Aβ(1–42) injections in the rat , 2002, Brain Research.

[40]  George A. Carlson,et al.  The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease , 2002, The Journal of Neuroscience.

[41]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[42]  B. Hyman,et al.  Reversible Memory Loss in a Mouse Transgenic Model of Alzheimer's Disease , 2002, The Journal of Neuroscience.

[43]  Xin Wu,et al.  Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model , 2002, Nature Neuroscience.

[44]  Jacob Raber,et al.  Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  D. Selkoe,et al.  The Many Faces of A: Structures and Activity , 2003 .

[46]  R. Anwyl,et al.  Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5 , 2004, The Journal of Neuroscience.

[47]  Edward A. Stern,et al.  Cortical Synaptic Integration In Vivo Is Disrupted by Amyloid-β Plaques , 2004, The Journal of Neuroscience.