DAILY PATTERNS OF CLOCK NEGATIVE FACTORS ARE MODIFIED IN THE HIPPOCAMPUS OF Aβ-INJECTED RAT

CANGIANO B; ANZULOVICH A; SANCHEZ M; GOMEZ MEJIBA SE; CORTEZ M; ALBA M; NAVIGATORE FONZO LS

Congreso; XL REUNION CIENTIFICA DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2022

Circadian disruption is prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment. At the molecular level,cellular oscillators consist of a network of interlocking transcriptional-translational feedback loops. The positive limb of the loopis represented by transcription factors, CLOCK, and BMAL1, which heterodimerize and bind to E-box sites in the promoters ofthe clock negative factors, period (PER1-3) and cryptochrome (CRY1-2) genes. A negative feedback loop is achieved when thePERs and CRYs form heterocomplexes that translocate back to the nucleus and inhibit their own and other clock-controlled genes'transcription. RevErbα and RORα transcription factors, members of the retinoic acid related orphan receptor (ROR) family,complete the molecular clock machinery. Previously, we found that an intracerebroventricular (i.c.v) injection of Aβ(1-42)modified the daily rhythms of BMAL1 and RORα expression and cognition-related factors in the rat hippocampus. Taking intoaccount those observations, the objective of this work was to investigate the effects of an i.c.v injection of amyloid beta peptide (1-42) on daily rhythms of PER1, PER2, CRY1 and CRY2 expression, as well as Aβ protein levels, in the rat hippocampus. In thisstudy, Holtzman male rats from control and Aβ-injected groups were sacrificed throughout a 24-h period and hippocampus sampleswere isolated every 6 h. Daily rhythms of clock genes expression were analyzed by RT-PCR and Aβ protein levels were analyzedby immunoblotting. Regulatory regions of clock PER1, PER2, CRY1, and CRY2 genes were scanned for E-box and RORE sites.We found that clock genes expression and Aβ levels displayed daily oscillations in the rat hippocampus. We found E-box andRORE sites on regulatory regions of clock genes. An i.c.v. injection of Aβ(1-42) modified daily rhythms of clock genes expressionand Aβ levels. Therefore, elevated levels of Aβ peptides could modify the temporal patterns of clock negative factors andconsequently could affect the transcription of genes related to cognition in AD.