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The effect of heat shock protein 72 on cognitive decline and metabolic health in the 5xFAD*Tg30 Alzheimer's disease model
Author(s) -
Marshall Jessica P.S.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038368
Subject(s) - genetically modified mouse , transgene , heat shock protein , endocrinology , presenilin , medicine , wild type , disease , biology , alzheimer's disease , gene , biochemistry , mutant
Abstract Background Heat shock protein 72 (HSP72) has the potential to play a cytoprotective role in Alzheimer’s disease (AD) as previous studies have demonstrated that its elevation inhibits amyloid beta oligomerization and enhances its clearance, restores tau homeostasis and inhibits neuronal apoptosis. BGP‐15 is a compound observed to be a co‐inducer of HSP72, and therefore, we hypothesized that pharmacological activating Hsp72 with this compound or genetically up‐regulating Hsp72 may be advantageous in preventing or delaying AD progression and associated pathology. Method We crossed 5xFAD (overexpressing human APP and Presenilin‐1) and Tg30 (overexpressing tau) mice, to create the double transgenic 5xFAD*Tg30. We then crossed the double transgenic mice with HSP72 overexpressing transgenic mice (Hsp72Tg) to create the triple transgenic, 5xFAD*Tg30*HSP72Tg. Double transgenic mice were kept untreated or treated with BGP‐15 in their drinking water in a randomised and blinded study in both male and female mice from the ages of 2‐10months. A comprehensive battery of behavioural and metabolic tests was conducted, and results compared to littermate wildtype mice. Result We observed significant declines in Rotarod, Y‐Maze and Novel Object performance in the 5xFAD*Tg30 mice compared to wildtype, however neither HSP72 overexpression or BGP‐15 treatment rescued this decline. HSP72 overexpression was effective in maintaining lean mass in male mice. BGP‐15 was efficacious in significantly increasing body weight specifically in female mice. In males there was a 40% decrease in survival rates by 10months, which was improved by BGP‐15 treatment to a 15% decrease(p=0.08). Conclusion BGP‐15 may improve survival rates (male) and increased weight (females) while overexpression of Hsp72 leads to maintenance of lean mass in male5xFAD*Tg30 mice. However, both avenues used to increase Hsp72 were insufficient to protect against cognitive deficits. Further studies analysing the brain pathology of these mice are warranted.