Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers.

Comprehending early amyloidogenesis is essential for the development of effective therapeutic strategies. In tauopathies like Alzheimer's disease (AD), the abnormal accumulation of tau protein is initiated by pathological tau seeds. Mounting evidence implies that the microtubule binding domain, consisting of three to four repeats, plays a pivotal role in this process, yet the exact region driving the formation of pathogenic species needs to be further scrutinized.

Modulation of Amyloid and Tau Aggregation to Alleviate Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease.

Aggregation of misfolded amyloid-β (Aβ) and hyperphosphorylated tau proteins to plaques and tangles, respectively, is the major drug target of Alzheimer's disease (AD), as the former is an onset biomarker and the latter is associated with neurodegeneration. Thus, we report a small molecule drug candidate, DN5355, with a dual-targeting function toward aggregates of both Aβ and tau. DN5355 was selected through a series of four screenings assessing 52 chemicals for their functions to inhibit and reverse the aggregation of Aβ and tau by utilizing thioflavin T.

A Therapeutic Nanovaccine that Generates Anti-Amyloid Antibodies and Amyloid-specific Regulatory T Cells for Alzheimer's Disease.

Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid-β (Aβ) plaque accumulation and neuroinflammation in the brain. The current immunotherapy approaches, such as anti-Aβ monoclonal antibody (mAb) therapy, Aβ vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, Aβ vaccines often induce T helper 1 (Th1) cell-mediated inflammatory responses.

Bias-generating factors in biofluid amyloid-β measurements for Alzheimer's disease diagnosis.

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, yet the dearth of readily accessible diagnostic biomarkers is a substantial hindrance towards progressing to effective preventive and therapeutic approaches. Due to a long delay between cerebral amyloid-β (Aβ) accumulation and the onset of cognitive impairments, biomarkers that reflect Aβ pathology and enable routine screening for disease progression are of urgent need for application in the clinical diagnosis of AD. According to accumulating evidences, cerebrospinal fluid (CSF) and plasma offer windows to the brain as they allow monitoring of biochemical changes in the brain.

Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aβ production and aggregation have been one of the most popular drug targets for AD.

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-β (Aβ), thioflavin S (ThS), a fluorescent dye with β-sheet binding properties, is widely employed to observe amyloid plaque accumulation. In this study, we investigated the possibility that a commonly used Aβ-expressing AD model mouse, 5XFAD, generates ThS-positive aggregates of β-sheet structures in addition to Aβ fibrils.