Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/ß-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/ß-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/ß-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/ß-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-ß (Aß) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/ß-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.

Nr4a1 regulates cell-specific transcriptional programs in inhibitory GABAergic interneurons.

The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of parvalbumin- and somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.

Solid-phase synthesis and pathological evaluation of pyroglutamate amyloid-ß3-42 peptide.

Pyroglutamate amyloid-ß3-42 (AßpE3-42) is an N-terminally truncated and pyroglutamate-modified Aß peptide retaining highly hydrophobic, amyloidogenic, and neurotoxic properties. In Alzheimer's disease (AD) patients, AßpE3-42 peptides accumulate into oligomers and induce cellular toxicity and synaptic dysfunction. AßpE3-42 aggregates further seed the formation of amyloid plaques, which are the pathological hallmarks of AD. Given that AßpE3-42 peptides play critical roles in the development of neurodegeneration, a reliable and reproducible synthetic access to these peptides may support pathological and medicinal studies of AD. Here, we synthesized AßpE3-42 peptides through the microwave-assisted solid-phase peptide synthesis (SPPS). Utilizing thioflavin T fluorescence assay and dot blotting analysis with anti-amyloid oligomer antibody, the amyloidogenic activity of synthesized AßpE3-42 peptides was confirmed. We further observed the cytotoxicity of AßpE3-42 aggregates in cell viability test. To examine the cognitive deficits induced by synthetic AßpE3-42 peptides, AßpE3-42 oligomers were intracerebroventricularly injected into imprinting control region mice and Y-maze and Morris water maze tests were performed. We found that AßpE3-42 aggregates altered the expression level of postsynaptic density protein 95 in cortical lysates. Collectively, we produced AßpE3-42 peptides in the microwave-assisted SPPS and evaluated the amyloidogenic and pathological function of the synthesized peptides.

Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model.

Transgenic mouse models recapitulating Alzheimer's disease (AD) pathology are pivotal in molecular studies and drug evaluation. In transgenic models selectively expressing amyloid-ß (Aß), thioflavin S (ThS), a fluorescent dye with ß-sheet binding properties, is widely employed to observe amyloid plaque accumulation. In this study, we investigated the possibility that a commonly used Aß-expressing AD model mouse, 5XFAD, generates ThS-positive aggregates of ß-sheet structures in addition to Aß fibrils. To test this hypothesis, brain sections of male and female 5XFAD mice were double-stained with ThS and monoclonal antibodies against Aß, tau, or α-synuclein, all of which aggregates are detected by ThS. Our results revealed that, in addition to amyloid plaques, 5XFAD mice express ThS-positive phospho-tau (p-tau) aggregates. Upon administration of a small molecule that exclusively disaggregates Aß to 5XFAD mice for six weeks, we found that the reduction level of plaques was smaller in brain sections stained by ThS compared to an anti-Aß antibody. Our findings implicate that the use of ThS complicates the quantification of amyloid plaques and the assessment of Aß-targeting drugs in 5XFAD mice.

Alzheimer's Disease Diagnosis Using Misfolding Proteins in Blood.

Alzheimer's disease (AD) is pathologically characterized by a long progressive phase of neuronal changes, including accumulation of extracellular amyloid-ß (Aß) and intracellular neurofibrillary tangles, before the onset of observable symptoms. Many efforts have been made to develop a blood-based diagnostic method for AD by incorporating Aß and tau as plasma biomarkers. As blood tests have the advantages of being highly accessible and low cost, clinical implementation of AD blood tests would provide preventative screening to presymptomatic individuals, facilitating early identification of AD patients and, thus, treatment development in clinical research. However, the low concentration of AD biomarkers in the plasma has posed difficulties for accurate detection, hindering the development of a reliable blood test. In this review, we introduce three AD blood test technologies emerging in South Korea, which have distinctive methods of heightening detection sensitivity of specific plasma biomarkers. We discuss in detail the multimer detection system, the self-standard analysis of Aß biomarkers quantified by interdigitated microelectrodes, and a biomarker ratio analysis comprising Aß and tau.

Bicine promotes rapid formation of ß-sheet-rich amyloid-ß fibrils.

Fibrillar aggregates of amyloid-ß (Aß) are the main component of plaques lining the cerebrovasculature in cerebral amyloid angiopathy. As the predominant Aß isoform in vascular deposits, Aß40 is a valuable target in cerebral amyloid angiopathy research. However, the slow process of Aß40 aggregation in vitro is a bottleneck in the search for Aß-targeting molecules. In this study, we sought a method to accelerate the aggregation of Aß40 in vitro, to improve experimental screening procedures. We evaluated the aggregating ability of bicine, a biological buffer, using various in vitro methods. Our data suggest that bicine promotes the aggregation of Aß40 with high speed and reproducibility, yielding a mixture of aggregates with significant ß-sheet-rich fibril formation and toxicity.

Preventive approach for overcoming dementia.

Dementia is used as a general term to describe chronic disorders of mental processes caused by the deterioration of cognitive functions to the extent that one's ability to perform daily activities is impaired. Currently, age is known to be the main risk factor for dementia, suggesting that the risk of being diagnosed with dementia significantly increases later in one's life. Therefore, there are two approaches one can take when confronting dementia: to cure it when it occurs in late adulthood or to prevent the onset of symptoms beforehand. Recently, the latter strategy of delaying and preventing Alzheimer's disease, the most prevalent form and most studied type of dementia, through both pharmaceutical and nonpharmaceutical interventions is becoming increasingly recognized. In this review, we discuss studies conducted in various fields that addresses nonpharmaceutical lifestyle interventions, including diet, physical activity, cognitive stimulation, and social engagement, and their effects in preventing and inhibiting dementia.