Circadian modulation by time-restricted feeding restores brain transcription and slows amyloid deposition in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology, hippocampal transcription, and memory in two transgenic mouse models of Alzheimer's disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aß42 clearance, improving sleep and memory, and normalizing time-of-day transcription of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the multifactorial effects of timed feeding, which has far-reaching impact beyond metabolism and affects the brain as the substrate for neurodegeneration, including the alignment of circadian rhythmicity. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression. Overall design: Prior to any measurements or beginning any experiments, mice were habituated to a 12:12 light-dark (LD 12:12) cycle and single housing conditions in custom light-tight cabinets. We then measured diurnal rhythms in activity and sleep behavior from the mice. To assess circadian impairments in the mice, some animals were placed in constant darkness (DD), followed by light masking and 6 h phase advance protocols. Feeding manipulations were then performed on mice habituated to LD 12:12. Animals within each sex and genotype were randomly divided into two groups with one group continuing ALF and the other placed on TRF, with food available during 6 h in the middle of the mouse active phase, during zeitgeber time (ZT) 15 to ZT21. By definition, ZT0 is the time when lights go on and ZT12 is the time when the lights go off when the mice are in a 12:12 LD cycle. After habituating to the feeding protocol, metabolites were measured in the mice to ensure the treatment was inducing the expected metabolic effects. The mice remained on TRF or ALF food access until sacrificed for tissue collection. After all tests were completed and the mice had re-entrained to the LD cycle, mice within each genotype and treatment group were randomly assigned for sacrifice at one of four time points: ZT0, ZT6, ZT12, or ZT18. ZT0 and ZT6 tissues were collected in the light; ZT12 and ZT18 were collected in the dark. Brain tissue and blood serum were collected for analysis. This study used a total of 110 mice almost equally distributed across sex/ genotype/treatment throughout the study, and further grouped by ZT collection times. Treated mice started TRF at6 to 9 months of age and were maintained on TRF until tissue collection, which occurred at 10 to 13 months of age.