Alzheimer’s Disease Aβ-Amyloid Plaque Morphology Varies According to APOE Isotype  

作　　者：Ina Caesar K. Peter R. Nilsson Per Hammarström Mikael Lindgren Stefan Prokop James Schmeidler Vahram Haroutunian David M. Holtzman Patrick R. Hof Sam Gandy Ina Caesar;K. Peter R. Nilsson;Per Hammarström;Mikael Lindgren;Stefan Prokop;James Schmeidler;Vahram Haroutunian;David M. Holtzman;Patrick R. Hof;Sam Gandy(Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Physics, Chemistry, and Biology, Linkö,ping University, Linkö,ping, Sweden;Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway;Department of Neuropathology, Charité Universitä,tsmedizin Berlin, Berlin, Germany;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA;James J. Peters VA Medical Center, Bronx, NY, USA;Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA;Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA)

机构地区：[1]Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2]Department of Physics, Chemistry, and Biology, Linkö,ping University, Linkö,ping, Sweden [3]Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway [4]Department of Neuropathology, Charité Universitä,tsmedizin Berlin, Berlin, Germany [5]Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [6]Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [7]James J. Peters VA Medical Center, Bronx, NY, USA [8]Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [9]Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA [10]Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

出　　处：《World Journal of Neuroscience》2023年第3期118-133,共16页神经科学国际期刊（英文）

摘　　要：Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.

关 键 词：Alzheimer’s Disease AMYLOID APOLIPOPROTEIN Luminescent Conjugated Oligothiophenes Hyperspectral Separation 

分 类 号：R74[医药卫生—神经病学与精神病学]