Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response.

Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.

Electrical stimulation of the ventral tegmental area evokes sleep-like state transitions under urethane anaesthesia in the rat medial prefrontal cortex via dopamine D1 -like receptors.

The role of dopamine in regulating sleep-state transitions during, both natural sleep and under anaesthesia, is still unclear. Recording in vivo in the rat mPFC under urethane anaesthesia, we observed predominantly slow wave activity (SWA) of <1 Hz in the local field potential interrupted by occasional spontaneous transitions to a low-amplitude-fast (LAF) pattern of activity. During periods of SWA, transitions to LAF activity could be rapidly and consistently evoked by electrical stimulation of the ventral tegmental area (VTA). Spontaneous LAF activity, and that evoked by stimulation of the VTA, consisted of fast oscillations similar to those seen in the rapid eye movement (REM)-like sleep state. Spontaneous and VTA stimulation-evoked LAF activity occurred simultaneously along the dorsoventral extent of all mPFC subregions. Evoked LAF activity depended on VTA stimulation current and could be elicited using either regular (25-50 Hz) or burst stimulation patterns and was reproducible upon repeated stimulation. Simultaneous extracellular single-unit recordings showed that during SWA, presumed pyramidal cells fired phasically and almost exclusively on the Up state, while during both spontaneous and VTA-evoked LAF activity, they fired tonically. The transition to LAF activity evoked by VTA stimulation depended on dopamine D1 -like receptor activation as it was almost completely blocked by systemic administration of the D1 -like receptor antagonist SCH23390. Overall, our data demonstrate that activation of dopamine D1 -like receptors in the mPFC is important for regulating sleep-like state transitions.

Pharmacological activation of the C5a receptor leads to stimulation of the ß-adrenergic receptor and alleviates cognitive impairment in a murine model of familial Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain causing either familial or sporadic dementia. We have previously administered the modified C5a receptor agonist (EP67) for a short period to a transgenic mouse model of AD (5XFAD) and have observed not only reduction in ß-amyloid deposition and gliosis but also improvement in cognitive impairment. Inquiring, however, on the effects of EP67 in an already heavily burdened animal, thus representing a more realistic scenario, we treated 6-month-old 5XFAD mice for a period of 14 weeks. We recorded a significant decrease in both fibrillar and pre-fibrillar ß-amyloid as well as remarkable amelioration of cognitive impairment. Following proteomic analysis and pathway association, we postulate that these events are triggered through the upregulation of ß-adrenergic and GABAergic signaling. In summary, our results reveal how inflammatory responses can be employed in inducing tangible phenotype improvements even in advanced stages of AD.

Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein.

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear. To determine whether early changes in sleep-related network activity could also be observed, prior to any previously reported cognitive dysfunction, we used mice that over-express human mutant α-syn (A30P). Recordings in vivo were performed under urethane anesthesia in the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus in young male (2.5 - 4 months old) A30P and age-matched wild type (WT) mice. We found that the slow oscillation (SO) < 1 Hz frequency was significantly faster in both the mPFC and hippocampus in A30P mice, and Up-state-associated fast oscillations at beta (20 - 30 Hz) and gamma (30 - 80 Hz) frequencies were delayed relative to the onset of the Up-state. Spindle (8 - 15 Hz) activity in the mPFC was also altered in A30P mice, as spindles were shorter in duration and had reduced density compared to WT. These changes demonstrate that dysregulation of sleep-related oscillations occurs in young A30P mice long before the onset of cognitive dysfunction. Our data suggest that, as seen in patients, changes in sleep-related oscillations are an early consequence of abnormal α-syn aggregation in A30P mice.

Quantitative electroencephalography as a marker of cognitive fluctuations in dementia with Lewy bodies and an aid to differential diagnosis.

OBJECTIVE: We investigated for quantitative EEG (QEEG) differences between Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) patients and healthy controls, and for QEEG signatures of cognitive fluctuations (CFs) in DLB. METHODS: We analysed eyes-closed, resting state EEGs from 18 AD, 17 DLB and 17 PDD patients with mild dementia, and 21 age-matched controls. Measures included spectral power, dominant frequency (DF), frequency prevalence (FP), and temporal DF variability (DFV), within defined EEG frequency bands and cortical regions. RESULTS: DLB and PDD patients showed a leftward shift in the power spectrum and DF. AD patients showed greater DFV compared to the other groups. In DLB patients only, greater DFV and EEG slowing were correlated with CFs, measured by the clinician assessment of fluctuations (CAF) scale. The diagnostic accuracy of the QEEG measures was 94% (90.4-97.9%), with 92.26% (80.4-100%) sensitivity and 83.3% (73.6-93%) specificity. CONCLUSION: Although greater DFV was only shown in the AD group, within the DLB group a positive DFV - CF correlation was found. QEEG measures could classify DLB and AD patients with high sensitivity and specificity. SIGNIFICANCE: The findings add to an expanding literature suggesting that EEG is a viable diagnostic and symptom biomarker in dementia, particularly DLB.