Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.

Introduction: Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.

Methods: To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.

Results: R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders.

Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment.

Background: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions.

Objective: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor.

Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model.

Reports from Alzheimer’s disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S- glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology.

Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

Introduction: Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).

Methods: We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).

Results: Baseline plasma Aβ was not related to cognitive or clinical progression.

Multiple types of cerebellar target neurons and their circuitry in the vestibulo-ocular reflex.

The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles.

Intrinsic physiology of identified neurons in the prepositus hypoglossi and medial vestibular nuclei.

Signal processing in the vestibular system is influenced by the intrinsic physiological properties of neurons that differ in neurotransmitters and circuit connections. Do membrane and firing properties differ across functionally distinct cell types? This study examines the intrinsic physiology of neurons in the medial vestibular nucleus (MVN) and nucleus prepositus hypoglossi (NPH) which express different neurotransmitters and have distinct axonal projections. NPH neurons expressing fluorescent proteins in glutamatergic, glycinergic, or GABAergic neurons were targeted for whole-cell patch recordings in brainstem slices obtained from transgenic mouse lines (YFP-16, GlyT2, and GIN).

Mechanisms of sustained high firing rates in two classes of vestibular nucleus neurons: differential contributions of resurgent Na, Kv3, and BK currents.

To fire at high rates, neurons express ionic currents that work together to minimize refractory periods by ensuring that sodium channels are available for activation shortly after each action potential. Vestibular nucleus neurons operate around high baseline firing rates and encode information with bidirectional modulation of firing rates up to several hundred Hz. To determine the mechanisms that enable these neurons to sustain firing at high rates, ionic currents were measured during firing by using the action potential clamp technique in vestibular nucleus neurons acutely dissociated from transgenic mice.

Glycinergic projection neurons of the cerebellum.

The cerebellum funnels its entire output through a small number of presumed glutamatergic premotor projection neurons in the deep cerebellar nuclei and GABAergic neurons that feed back to the inferior olive. Here we use transgenic mice selectively expressing green fluorescent protein in glycinergic neurons to demonstrate that many premotor output neurons in the medial cerebellar (fastigial) nuclei are in fact glycinergic, not glutamatergic as previously thought. These neurons exhibit similar firing properties as neighboring glutamatergic neurons and receive direct input from both Purkinje cells and excitatory fibers.