Rational Development of a Small-Molecule Activator of CK1γ2 That Decreases C99 and Beta-Amyloid Levels.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD.

Task-selective place cells show behaviorally driven dynamics during learning and stability during memory recall.

Decades of work propose that hippocampal activity supports internal representation of learned experiences and contexts, allowing individuals to form long-term memories and quickly adapt behavior to changing environments. However, recent studies insinuate hippocampal representations can drift over time, raising the question: how could the hippocampus hold stable memories when activity of its neuronal maps fluctuates? We hypothesized that task-dependent hippocampal maps set by learning rules and structured attention stabilize as a function of behavioral performance. To test this, we imaged hippocampal CA1 pyramidal neurons during learning and memory recall phases of a new task where mice use odor cues to navigate between two reward zones.

C99 selectively accumulates in vulnerable neurons in Alzheimer's disease.

Introduction: The levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer's disease (AD) progression. Therefore, it is likely that amyloid precursor protein and its proteolytic fragments other than amyloid b (Ab) contribute to the onset of AD.

Methods: We developed a sensitive assay adapted to the detection of C99, the direct precursor of b-amyloid.