Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer's Disease / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To review recent research advances on tau, a major player in Alzheimer's disease (AD) pathogenesis, a biomarker for AD onset, and potential target for AD therapy.</p><p><b>DATA SOURCES</b>This review was based on a comprehensive search using online literature databases, including PubMed, Web of Science, and Google Scholar.</p><p><b>STUDY SELECTION</b>Literature search was based on the following keywords: Alzheimer's disease, tau protein, biomarker, cerebrospinal fluid (CSF), therapeutics, plasma, imaging, propagation, spreading, seeding, prion, conformational templating, and posttranslational modification. Relevant articles were carefully reviewed, with no exclusions applied to study design and publication type.</p><p><b>RESULTS</b>Amyloid plaques enriched with extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks of AD. Although the Aβ hypothesis has dominated AD research for many years, clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset. The research focus in AD has recently shifted to the role of tau in AD. In addition to phosphorylation, tau is acetylated and proteolytically cleaved, which also contribute to its physiological and pathological functions. Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis. Techniques to detect tau at minute levels in CSF and blood have been developed, and improved tracers have facilitated tau imaging in the brain. These advances have potential to accurately determine tau levels at early diagnostic stages in AD. Given that tau is a potential therapeutic target, anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.</p><p><b>CONCLUSION</b>Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.</p>

Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.</p><p><b>METHODS</b>The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence.</p><p><b>RESULTS</b>In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation.</p><p><b>CONCLUSIONS</b>oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.</p>

Reduction of Glucose Metabolism in Olfactory Bulb is an Earlier Alzheimer's Disease-related Biomarker in 5XFAD Mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Early diagnosis assumes a vital role in an effective treatment of Alzheimer's disease (AD). Most of the current studies can only make an AD diagnosis after the manifestation of typical clinical symptoms. The present study aimed to investigate typical and other biomarkers of AD to find a possible early biomarker.</p><p><b>METHODS</b>A total of 14 5XFAD mice (at 3 and 6 months old), with 14 age-matched wild-type (WT) mice as control, were enrolled in this case-control study. Morris water maze test was performed to evaluate the cognitive function; buried food pellet test and olfactory maze test were employed to investigate the olfactory function; immunofluorescence to detect amyloid deposition and positron emission tomography to examine 2-deoxy-2-(18F) fluoro-D-glucose ([18F]-FDG) uptake in the hippocampus and cerebral cortex.</p><p><b>RESULTS</b>With the increasing age, cognitive performance (P = 0.0262) and olfactory function were significantly deteriorated (day 1 P = 0.0012, day 2 P = 0.0031, day 3 P = 0.0160, respectively) and the (18F)-FDG uptake was markedly decreased in multi-cerebral regions including the olfactory bulb (P < 0.0001), hippocampus (P = 0.0121), and cerebral cortex (P < 0.0001). Of note, in 3-month-old 5XFAD mice, a significant decline of (18F)-FDG uptake in the olfactory bulb was found when compared with that of age-matched WT mice (P = 0.023) while no significant difference was present when the uptakes in other cerebral regions were compared.</p><p><b>CONCLUSIONS</b>The decline of (18F)-FDG uptake in the olfactory bulb occurs earlier than other incidents, serving as an earlier in vivo biological marker of AD in 5XFAD mice and making early diagnosis of AD possibly.</p>