TY - JOUR
T1 - Fingolimod Rescues Memory and Improves Pathological Hallmarks in the 3xTg-AD Model of Alzheimer’s Disease
AU - Fagan, Steven G.
AU - Bechet, Sibylle
AU - Dev, Kumlesh K.
N1 - Funding Information:
Funding for this project was supplied by the Health Research Board of Ireland.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - Therapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.
AB - Therapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.
KW - Alzheimer’s disease
KW - FTY720
KW - Inflammation
KW - Sphingosine-1-phosphate
UR - http://www.scopus.com/inward/record.url?scp=85123183641&partnerID=8YFLogxK
U2 - 10.1007/s12035-021-02613-5
DO - 10.1007/s12035-021-02613-5
M3 - Article
C2 - 35031916
AN - SCOPUS:85123183641
SN - 0893-7648
VL - 59
SP - 1882
EP - 1895
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -