Current Alzheimer research最新文献

Alzheimer's disease (AD) is a highly hereditary disease with complex genetic susceptibility factors. Extensive genome-wide association studies have established a distinct susceptibility link between the protein tyrosine kinase 2β (PTK2B) gene and late-onset Alzheimer's disease (LOAD), but the specific pathogenic mechanisms remain incompletely understood. PTK2B is known to be expressed in neurons, and recent research has revealed its more important significance in microglia. Elucidating the role of PTK2B high expression in microglia in AD's progression is crucial for uncovering novel pathogenic mechanisms of the disease. Our review of existing studies suggests a close relationship between PTK2B/proline-rich tyrosine kinase 2 (Pyk2) and tau pathology, and this process might be β-amyloid (Aβ) dependence. Pyk2 is hypothesized as a pivotal target linking Aβ and tau pathologies. Concurrently, Aβ-activated Pyk2 participates in the regulation of microglial activation and its proinflammatory functions. Consequently, it is reasonable to presume that Pyk2 in microglia contributes to amyloid-induced tau pathology in AD via a neuroinflammatory pathway. Furthermore, many things remain unclear, such as identifying the specific pathways that lead to the release of downstream inflammatory factors due to Pyk2 phosphorylation and whether all types of inflammatory factors can activate neuronal kinase pathways. Additionally, further in vivo experiments are essential to validate this hypothesized pathway. Considering PTK2B/Pyk2's potential role in AD pathogenesis, targeting this pathway may offer innovative and promising therapeutic approaches for AD.

Psychosis and hyperactive behaviors, such as agitation and wandering, affect a significant proportion of patients with Alzheimer's disease (AD). These symptoms are often treated with antipsychotics, usually in an off-label approach. This mini-review provides an updated perspective on the pharmacological approach for the neuropsychiatric symptoms (NPS) in AD. The results of new studies have provided a better understanding of AD-related NPS management, but high-quality evidence still needs to be obtained. Herein, we argue for a more cautious approach to the use of antipsychotics in AD and highlight the importance of exploring alternative treatments for NPS. By doing so, we can ensure that patients with AD receive optimal care that is both effective and safe.

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The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis. The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer's disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term "PERK-opathies" is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders.