👤 Melek Altunkaya

The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume. Show less

In our research, we examined how the induction of long-term potentiation (LTP) in the hippocampus of hypothyroid rats afects the mRNA levels of several proteins involved with neurodegeneration, including Gsk3, Cdk5, Akt1, Mapt, P35 (Anxa), Capn1, Bace1, and Psen2. Wistar-albino rats, consisting of 12 males, were used in the research, and they were separated into 2 groups: control (n=6) and hypothyroidism (n=6). To induce hypothyroidism, propylthiouracil was added to drinking water at a dosage of 20 mg/kg/day. The test stimulus intensity was calculated, basal recordings were acquired, and LTP was induced by administering 100 Hz high-frequency stimulation (HFS) for 1 second with a 5-minute delay when the rats were aged 60 days. The population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope were measured in the granule cell layer of the dentate gyrus. Using reverse transcription polymerase chain reaction, the mRNA levels of neurodegenerative genes were assessed in induced hippocampal tissues after the LTP protocol. The free T4 levels in plasma were measured using a plate reader with the commercial ELISA kit. Following HFS, LTP was solely induced in the EPSP slope and PS amplitude in the control group. The impaired LTP response of the hypothyroidism group was accompanied by an increase in Akt1-mRNA expression and a decrease in Gsk3ß expression, whereas the value genes' mRNA expression levels did not difer significantly from those of the control group. The hypothyroidism-related LTP impairment could be caused by a reduction in PI3K/AKT signaling. Further investigation of this path is required to elucidate the pathophysiology of impaired synaptic plasticity in hypothyroidism. Show less

Thyroid hormones, which produce critical changes in our bodies even when their physiological levels alter slightly, are crucial hormones that influence gene transcription. Neuronal plasticity, on the other hand, requires both the activation of local proteins as well as protein translation and transcription in response to external signals. So far, no study has examined metaplastic long-term potentiation (LTP) and related gene expression levels in a hyperthyroid experimental model. The Wistar male rats were administered 0.2 mg/kg/day of l-thyroxine for 21 days to induce hyperthyroidism. Perforant path was primed with 1-Hz low-frequency stimuli (LFS) for 900 s to investigate metaplasticity responses. The LFS was followed by high-frequency stimuli (HFS, 100 Hz) after 5 min. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were recorded from the granule cell layer of the dentate gyrus. The mRNA levels of genes related to neurodegeneration (Gsk-3β, Cdk5, Akt1, Mapt, p35, Capn1, Bace1, and Psen2) were measured using the RT-PCR method for the stimulated hippocampus. Similar to euthyroid rats, hyperthyroid animals had a lower EPSP slope and PS after LFS. Depression of EPSP prevented subsequently induced EPSP-LTP, although HFS was able to elicit PS-LTP despite depression of PS amplitude in both groups. Despite similarities in metaplastic LTP responses, these electrophysiological findings were accompanied by increased Akt, Bace1, Cdk5, and p35-mRNA expressions and decreased Gsk-3β mRNA expression in hyperthyroid rats' hippocampus. These data support the view that in thyroid hormone excess, the mechanism that keeps synaptic efficacy within a dynamic range occurs concurrently with increased mRNA expression of neurodegeneration-related genes. Our study encourages further examination of the increased risk of neurodegenerative disease in hyperthyroidism. Show less