TY - JOUR
T1 - Evaluation of Memantine in AAV-AD Rat
T2 - A Model of Late-Onset Alzheimer’s Disease Predementia
AU - Souchet, B.
AU - Audrain, M.
AU - Alves, S.
AU - Fol, R.
AU - Tada, S.
AU - Orefice, N. S.
AU - Potier, B.
AU - Dutar, P.
AU - Billard, J. M.
AU - Cartier, Nathalie
AU - Braudeau, Jérôme
N1 - Publisher Copyright:
© 2022, Serdi and Springer Nature Switzerland AG.
PY - 2022/4
Y1 - 2022/4
N2 - Background: Though our understanding of Alzheimer’s disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer’s Disease (LOAD). Objectives: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. Methods: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer’s pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. Results: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. Conclusions: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.
AB - Background: Though our understanding of Alzheimer’s disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer’s Disease (LOAD). Objectives: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. Methods: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer’s pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. Results: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. Conclusions: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.
KW - AAV-AD rat
KW - LOAD
KW - animal model
KW - memantine
KW - prevention
UR - http://www.scopus.com/inward/record.url?scp=85123465082&partnerID=8YFLogxK
U2 - 10.14283/jpad.2021.67
DO - 10.14283/jpad.2021.67
M3 - Article
C2 - 35543008
AN - SCOPUS:85123465082
SN - 2426-0266
VL - 9
SP - 338
EP - 347
JO - The journal of prevention of Alzheimer's disease
JF - The journal of prevention of Alzheimer's disease
IS - 2
ER -