Multiple amyloid binding sites in Alzheimer brain and their interaction with synaptic and inflammatory mechanisms

<p>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. </p><p>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). </p><p>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). </p><p>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). </p><p>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). </p><p>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.</p><h3>List of scientific papers</h3><p>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. <br><a href="https://doi.org/10.1093/brain/awt142">https://doi.org/10.1093/brain/awt142</a><br><br> </p><p>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]</p><p>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]</p><p>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. <br><a href="https://doi.org/10.3233/JAD-2012-121489">https://doi.org/10.3233/JAD-2012-121489</a><br><br> </p><p>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. <br><a href="https://doi.org/10.3233/JAD-2012-121447">https://doi.org/10.3233/JAD-2012-121447</a><br><br> </p>