Modeling the early stages of Alzheimer's disease by administering intracerebroventricular injections of human native A beta oligomers to rats
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Modeling the early stages of Alzheimer's disease by administering intracerebroventricular injections of human native A beta oligomers to rats. / Baerends, Eva; Soud, Katia; Folke, Jonas; Pedersen, Anna-Kathrine; Henmar, Simon; Konrad, Lisa; Lycas, Matthew D.; Mori, Yuki; Pakkenberg, Bente; Woldbye, David P. D.; Dmytriyeva, Oksana; Pankratova, Stanislava.
In: Acta Neuropathologica Communications, Vol. 10, No. 1, 113, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Modeling the early stages of Alzheimer's disease by administering intracerebroventricular injections of human native A beta oligomers to rats
AU - Baerends, Eva
AU - Soud, Katia
AU - Folke, Jonas
AU - Pedersen, Anna-Kathrine
AU - Henmar, Simon
AU - Konrad, Lisa
AU - Lycas, Matthew D.
AU - Mori, Yuki
AU - Pakkenberg, Bente
AU - Woldbye, David P. D.
AU - Dmytriyeva, Oksana
AU - Pankratova, Stanislava
PY - 2022
Y1 - 2022
N2 - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease characterized by the accumulation of aggregated amyloid beta (A beta) and hyperphosphorylated tau along with a slow decline in cognitive functions. Unlike advanced AD, the initial steps of AD pathophysiology have been poorly investigated, partially due to limited availability of animal models focused on the early, plaque-free stages of the disease. The aim of this study was to evaluate the early behavioral, anatomical and molecular alterations in wild-type rats following intracerebroventricular injections of human A beta oligomers (A beta Os). Bioactive human AD and nondemented control brain tissue extracts were characterized using ELISA and proteomics approaches. Following a bilateral infusion, rats underwent behavioral testing, including the elevated plus maze, social recognition test, Morris water maze and Y-maze within 6 weeks postinjection. An analysis of brain structure was performed with manganese-enhanced MRI. Collected brain tissues were analyzed using stereology, immunohistochemistry, ELISA and qPCR. No sensorimotor deficits affecting motor performance on different maze tasks were observed, nor was spatial memory disturbed in AD rats. In contrast, a significant impairment of social memory became evident at 21 days postinjection. This deficit was associated with a significantly decreased volume of the lateral entorhinal cortex and a tendency toward a decrease in the total brain volume. Significant increase of cleaved caspase-3-positive cells, microglial activation and proinflammatory responses accompanied by altered expression of synaptic markers were observed in the hippocampus of AD rats with immunohistochemical and qPCR approaches at 6 weeks postinjection. Our data suggest that the social memory impairment observed in A beta O-injected rats might be determined by neuroinflammatory responses and synaptopathy. An infusion of native oligomeric A beta in the rat brain represents a feasible tool to model early plaque-free events associated with AD.
AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease characterized by the accumulation of aggregated amyloid beta (A beta) and hyperphosphorylated tau along with a slow decline in cognitive functions. Unlike advanced AD, the initial steps of AD pathophysiology have been poorly investigated, partially due to limited availability of animal models focused on the early, plaque-free stages of the disease. The aim of this study was to evaluate the early behavioral, anatomical and molecular alterations in wild-type rats following intracerebroventricular injections of human A beta oligomers (A beta Os). Bioactive human AD and nondemented control brain tissue extracts were characterized using ELISA and proteomics approaches. Following a bilateral infusion, rats underwent behavioral testing, including the elevated plus maze, social recognition test, Morris water maze and Y-maze within 6 weeks postinjection. An analysis of brain structure was performed with manganese-enhanced MRI. Collected brain tissues were analyzed using stereology, immunohistochemistry, ELISA and qPCR. No sensorimotor deficits affecting motor performance on different maze tasks were observed, nor was spatial memory disturbed in AD rats. In contrast, a significant impairment of social memory became evident at 21 days postinjection. This deficit was associated with a significantly decreased volume of the lateral entorhinal cortex and a tendency toward a decrease in the total brain volume. Significant increase of cleaved caspase-3-positive cells, microglial activation and proinflammatory responses accompanied by altered expression of synaptic markers were observed in the hippocampus of AD rats with immunohistochemical and qPCR approaches at 6 weeks postinjection. Our data suggest that the social memory impairment observed in A beta O-injected rats might be determined by neuroinflammatory responses and synaptopathy. An infusion of native oligomeric A beta in the rat brain represents a feasible tool to model early plaque-free events associated with AD.
KW - Alzheimer's disease
KW - Social recognition
KW - Hippocampus
KW - Lateral entorhinal cortex
KW - Neuroinflammation
KW - DEPENDENT PROTEIN-KINASE
KW - LONG-TERM POTENTIATION
KW - IMPAIR SYNAPTIC PLASTICITY
KW - AMYLOID-BETA
KW - COGNITIVE DECLINE
KW - MOUSE MODEL
KW - INTRACEREBRAL INFUSION
KW - SOLUBLE OLIGOMERS
KW - APOLIPOPROTEIN-E
KW - SOCIAL MEMORY
U2 - 10.1186/s40478-022-01417-5
DO - 10.1186/s40478-022-01417-5
M3 - Journal article
C2 - 35974377
VL - 10
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
SN - 2051-5960
IS - 1
M1 - 113
ER -
ID: 317426809