Long-term dietary interventions fail to mitigate functional connectivity loss and cognitive decline in the TgF344-AD rat model of Alzheimers Disease

Abstract

IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder, characterized by altered brain functional connectivity and network activity, detectable using resting-state functional MRI (rsfMRI). Caloric restriction (CR) and its mimetic resveratrol (Rsv) have shown potential in reducing AD-related pathology and preserving brain function, though research on long-term efficacy is limited. Therefore, we aimed to assess the effects of short- term CR and Rsv administrations on resting-state (rs) functional connectivity (FC), after which we assessed the effects of long-term CR and Rsv interventions on rs-FC, spatial memory, amyloid burden, and neuroinflammation in TgF344-AD rats (Tg) and wild-type (WT) littermates. Materials and MethodsWe used rsfMRI to investigate rs-FC changes after CR (40%) or daily Rsv supplementation (10 mg/kg, oral) in male and female, WT and TgF344-AD (Tg) rats at the age of 4 months and 11 months, after, respectively, 1 month (short-term) and 8 months (long- term) of either Rsv supplementation, control (Ctrl) or CR diet. Additionally, spatial memory was assessed utilizing the Morris Water Maze (MWM), followed by histological validation of amyloid plaque load (X34), astrogliosis (GFAP) and microgliosis (IBA-1) at 11 months of age. ResultsBoth long-term CR or Rsv supplementation exert limited effects in the TgF344-AD model on the known AD-related pathological hallmarks. Short-term CR led to a reduction in rs-FC in female TgF344-AD rats compared to Rsv Tg supplemented rats for connections primarily within and between the hippocampal network, while between other connections, CR reduced rs-FC compared to Ctrl in females, irrespective of genotype. Rsv increased rs-FC compared to CR for only a few connections in females, again irrespective of genotype. Long- term CR decreased rs-FC in male Tg CR rats, compared to Tg Ctrl and WT CR rats, primarily for connections within the lateral cortical network (LCN). For other connections, CR reduced rs- FC when compared to Ctrl, irrespective of genotype. Overall, Rsv supplementation showed negligible effects on rs-FC. Moreover, long-term CR yielded modest cognitive improvements in male Tg rats, as evidenced by enhanced performance in the MWM but not in females. Histological validation after long-term dietary intervention revealed region-specific increase or decrease of amyloid burden after CR or Rsv supplementation, respectively. Additionally, CR reduced IBA-1 levels in males, irrespective of genotype, GFAP levels were unaffected by long- term dietary intervention. ConclusionAltogether, our findings indicate that long-term CR and Rsv exert distinct and limited effects on AD-related pathology in the TgF344-AD model, with CR demonstrating a modest but greater effect on functional and cognitive measures compared to Rsv. This study underscores the difficulty of altering key disease processes with these long-term dietary approaches, highlighting the need for more comprehensive long-term studies to elucidate the potential modulatory role of dietary interventions on AD pathophysiology.