A lifespan observation of a novel mouse model: in vivo evidence supports aβ oligomer hypothesis.
Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China.
Yichi
Y
Zhang
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China.
Lu
L
Lu
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China ; Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China ; Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, China.
Jianping
J
Jia
Department of Neurology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, China.
Longfei
L
Jia
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois, United States of America.
Changiz
C
Geula
Department of Neurobiology, Karolinska Institutet, Stockholm, Sweden.
Jinjing
J
Pei
Department of Neurobiology, Capital Medical University, Beijing, China.
Zhiqing
Z
Xu
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China ; Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China ; Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, China.
Wei
W
Qin
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China ; Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China ; Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, China.
Ruiqin
R
Liu
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China ; Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China ; Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, China.
Dan
D
Li
Department of Neurobiology, Capital Medical University, Beijing, China.
Na
N
Pan
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008136:Longevity; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D023421:Models, Animal; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D055503:Protein Multimerization; D013569:Synapses / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins