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 ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß 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. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment 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. Across learning, both orthogonal and overlapping task-dependent place maps form rapidly, discriminating trial context with strong correlation to behavioral performance. Once formed, task-selective place maps show increased long-term stability during memory recall phases. We conclude that memory demand and attention stabilize hippocampal activity to maintain contextually rich spatial representations.

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. Three postmortem groups were studied: control with normal and stable cognition; patients with moderate AD, and individuals with severe AD. The amount of C99 and Aß was quantified and correlated with the severity of AD. RESULTS: C99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, Aß levels are increased in both vulnerable and resistant brain areas. DISCUSSION: These results raise the possibility that C99, rather than Aß plaques, is responsible for the death of nerve cells in AD.