Multiple amyloid binding sites in Alzheimer brain and their interaction with synaptic and inflammatory mechanisms
Author: Ni, Ruiqing
Date: 2015-03-31
Location: Hörsalen Novum 4th floor, Karolinska Institutet, Huddinge
Time: 09.30
Department: Inst för neurobiologi, vårdvetenskap och samhälle / Dept of Neurobiology, Care Sciences and Society
Abstract
Alzheimer’s disease (AD) is the most common type of dementia. A series of pathophyslogical changes start many years prior to the emergence of clinical symptoms. The main aims of this thesis were to investigate fibrillar amyloid-β _imaging tracers that bind to the AD brain and the relationships between amyloid pathology, inflammation, and synaptic changes in AD.
Amyloid-β _plaque deposition is one of the pathological hallmarks of AD. We demonstrated that amyloid positron emission tomography (PET) tracers 3H-Pittsburgh compound B (PIB), BTA-1, florbetaben, florbetapir and AZD2184 detect a similar high-affinity site and a varying low-affinity binding site on fibrillar amyloid-β _in postmortem sporadic AD brain. Autosomal dominant AD showed an additional binding site with AZD2184 in the frontal cortex and higher 3H-PIB binding in the striatum than in sporadic AD. Amyloid tracer binding to fibrillar Aβ _was influenced by resveratrol and AZD2184 showed the greatest changes. These findings suggest a multiple binding site model for amyloid tracers in the AD brain (Papers I, II).
Inflammation is recognized to play a crucial role in AD. Cross-sectional microPET imaging in APPswe transgenic AD mice showed increased 11C-deuterium-L-deprenyl PET binding (astrocytosis) at 6 months compared to age-matched wild-type mice, prior to the increase in 11C-AZD2184 PET retention (amyloid-β _plaque deposition) that occurred at 18-24 months, suggesting that astrocytosis is an early event in comparison to amyloid-β _plaque deposition. In vitro autoradiography and immunochemistry staining confirmed age-related increases in Aβ deposits and indicated a context-dependent astrocytosis in transgenic AD mice (Paper III).
Mild cognitive impairment is prodromal stage of AD. We found that the combination of measurement of parietal glucose metabolism using the neurodegeneration biomarker 18F-fluorodeoxyglucose PET with analysis of total tau levels in cerebrospinal fluid provided the best prediction of patients with mild cognitive impairment converting to AD (Paper IV).
Aβ assemblies bind to α7_ _nicotinic acetylcholine receptors (nAChRs) and form complexes in the AD brain. 3H-PIB measurements showed increased fibrillar Aβ _levels in the presence of α7 nAChR agonists, suggesting a specific interaction between fibrillar amyloid-β _and α7 nAChRs, and α7 nAChR drugs may influence on the fibrillar Aβ-α7 nAChR interaction (Paper V).
In conclusion, clinical amyloid tracers detect multiple binding sites on fibrillar amyloid-β _in the AD brain. Amyloid-β _interacts with astrocytosis and synaptic sites. A deeper understanding of the subtle difference of amyloid-β _binding sites in brain could facilitate the development of amyloid-β _tracers and drugs for AD.
Amyloid-β _plaque deposition is one of the pathological hallmarks of AD. We demonstrated that amyloid positron emission tomography (PET) tracers 3H-Pittsburgh compound B (PIB), BTA-1, florbetaben, florbetapir and AZD2184 detect a similar high-affinity site and a varying low-affinity binding site on fibrillar amyloid-β _in postmortem sporadic AD brain. Autosomal dominant AD showed an additional binding site with AZD2184 in the frontal cortex and higher 3H-PIB binding in the striatum than in sporadic AD. Amyloid tracer binding to fibrillar Aβ _was influenced by resveratrol and AZD2184 showed the greatest changes. These findings suggest a multiple binding site model for amyloid tracers in the AD brain (Papers I, II).
Inflammation is recognized to play a crucial role in AD. Cross-sectional microPET imaging in APPswe transgenic AD mice showed increased 11C-deuterium-L-deprenyl PET binding (astrocytosis) at 6 months compared to age-matched wild-type mice, prior to the increase in 11C-AZD2184 PET retention (amyloid-β _plaque deposition) that occurred at 18-24 months, suggesting that astrocytosis is an early event in comparison to amyloid-β _plaque deposition. In vitro autoradiography and immunochemistry staining confirmed age-related increases in Aβ deposits and indicated a context-dependent astrocytosis in transgenic AD mice (Paper III).
Mild cognitive impairment is prodromal stage of AD. We found that the combination of measurement of parietal glucose metabolism using the neurodegeneration biomarker 18F-fluorodeoxyglucose PET with analysis of total tau levels in cerebrospinal fluid provided the best prediction of patients with mild cognitive impairment converting to AD (Paper IV).
Aβ assemblies bind to α7_ _nicotinic acetylcholine receptors (nAChRs) and form complexes in the AD brain. 3H-PIB measurements showed increased fibrillar Aβ _levels in the presence of α7 nAChR agonists, suggesting a specific interaction between fibrillar amyloid-β _and α7 nAChRs, and α7 nAChR drugs may influence on the fibrillar Aβ-α7 nAChR interaction (Paper V).
In conclusion, clinical amyloid tracers detect multiple binding sites on fibrillar amyloid-β _in the AD brain. Amyloid-β _interacts with astrocytosis and synaptic sites. A deeper understanding of the subtle difference of amyloid-β _binding sites in brain could facilitate the development of amyloid-β _tracers and drugs for AD.
List of papers:
I. Ni R, Gillberg PG, Bergfors A, Marutle A, Nordberg A. Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue. Brain. 2013;136:2217-27.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ni R, Gillberg PG, Viitanen M, Myllykangas L, Bogdanovic N, Långström B, Nordberg A. Discrimination between clinical amyloid tracers and resveratrol in familial and sporadic Alzheimer disease. [Manuscript]
III. Rodriguez-Vieitez, E, Ni R, Gulyás B, Tóth M, Häggkvist J, Halldin C, Voytenko L, Marutle A, Nordberg A. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. [Submitted]
IV. Choo IH, Ni R, Schöll M, Wall A, Almkvist O, Nordberg A. Combination of (18)F-FDG PET and cerebrospinal fluid biomarkers as a better predictor of the progression to Alzheimer's disease in mild cognitive impairment patients. J Alzheimers Dis. 2013;33(4):929-39.
Fulltext (DOI)
Pubmed
V. Ni R, Marutle A, Nordberg A. Modulation of alpha7 nicotinic acetylcholine receptor and fibrillar amyloid-beta interactions in Alzheimer's disease brain. J Alzheimers Dis. 2013;33(3):841-51.
Fulltext (DOI)
Pubmed
I. Ni R, Gillberg PG, Bergfors A, Marutle A, Nordberg A. Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue. Brain. 2013;136:2217-27.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ni R, Gillberg PG, Viitanen M, Myllykangas L, Bogdanovic N, Långström B, Nordberg A. Discrimination between clinical amyloid tracers and resveratrol in familial and sporadic Alzheimer disease. [Manuscript]
III. Rodriguez-Vieitez, E, Ni R, Gulyás B, Tóth M, Häggkvist J, Halldin C, Voytenko L, Marutle A, Nordberg A. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. [Submitted]
IV. Choo IH, Ni R, Schöll M, Wall A, Almkvist O, Nordberg A. Combination of (18)F-FDG PET and cerebrospinal fluid biomarkers as a better predictor of the progression to Alzheimer's disease in mild cognitive impairment patients. J Alzheimers Dis. 2013;33(4):929-39.
Fulltext (DOI)
Pubmed
V. Ni R, Marutle A, Nordberg A. Modulation of alpha7 nicotinic acetylcholine receptor and fibrillar amyloid-beta interactions in Alzheimer's disease brain. J Alzheimers Dis. 2013;33(3):841-51.
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Nordberg, Agneta
Issue date: 2015-03-09
Rights:
Publication year: 2015
ISBN: 978-91-7549-873-7
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