AGING CELL: The team found that the longevity gene Klotho improves the removal and cognition of A-beta in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic age-related neurodegenerative disease characterized by elderly plaque deposition, intracellular nerve fiber entanglement, and decreased sexual cognitive function.
more than 50 million AD patients have been diagnosed worldwide as of 2018.
hypothesis has been put forward to explain the cause and pathogenesis of Alzheimer's disease.
the amyloid protein-beta (A beta) cascading hypothesis is the mainstream hypothesis that has explained the pathogenesis of AD over the past two decades.
the production and removal of a beta peptide in the brains of AD patients, which then form amyloid plaques and lead to neuron dysfunction.
A-beta deficiency, rather than A-beta over-generation, is considered a major cause of disease, and over-generation of A-beta can lead to neuroinstitive, aggressive synapse loss, and ultimately cognitive decline.
studies have shown that A-beta activates NACHT, LRR, and PYD-containing protein 3 (NLRP3) inflammatory bodies, mediates the transition of small glial cells from M2 to M1, reducing the removal of A-beta.
, a vicious feedback loop is formed between the activation of the inflammatory body of A beta and NLRP3, leading to a gradual deterioration of the patient's condition.
changes in the expression or activity of excret transporters (e.g., LDL-related proteins 1 (LRP1), P-glycoprotein (P-gp) and triphosphate adenosine (ATP) binding box transporters A1 (ABCA1)) and late glycation end products (RAGE) were observed in AD patients and mouse models, leading to the removal of A-beta barriers.
inhibits the NLRP3/caspase-1 axis and enhances transporter-mediated A-beta removal, which theoretically prevents AD from occurring.
previous studies have shown that the anti-aging gene Klotho is highly expressed in the kidneys and veins and lower in the brain.
Klotho has a variety of physiological functions, such as anti-neuro-inflammatory effects and regulation of autophagy.
previous studies have shown that Klotho in the brains of AD patients and mice was significantly lower than the age-matching healthy group.
more studies have provided signs that Klotho may relieve a range of neurodegenerative diseases.
these findings provide compelling evidence that Klotho may be the target of AD's new treatment.
in a previous study, researchers maintained Klotho in the brain for up to three months in a 7-month-old amyloid prelogum protein/resenilin 1 (APP/PS1) mouse model, significantly reducing beta levels and cognitive impairment.
, the impact and potential mechanisms of the long-term Klotho increase on AD's late stages remain unclear.
based on accumulated evidence of Klotho's anti-AD effects, researchers from Sichuan University speculated that Klotho improved A-beta pathology and cognitive dysfunction by promoting the transformation of small glial cells from M1 to M2.
to test this hypothesis, the researchers induced Klotho over-expression in the brains of 13-month-old APP/PS1 mice by injecting a phovirus carrying lotho cDNA from the brain's side of the brain.
, the researchers explored the effects of Klotho over-expression on mouse cognition, A-beta burden, A-beta-related neuropathology, small glial cell transformation, and A-beta transport systems.
addition, the researchers studied Klotho's effect on beta transport at the blood-cerebrospinal fluid barrier by knocking out Klotho from HCPEpiCs.
results showed that an increase in Klotho levels in the brain and serum significantly improved the A-beta burden, neuron and synth loss, and cognitive impairment in older APP/PS1 mice.
Klotho therapy significantly inhibits NACHT, LRR, and PYD-containing domain protein 3 (NLRP3), as well as the subsequent conversion of small glial cells to M2, which may enhance the A-beta removal mediated by small glial cells.
, Klotho over-expression also regulates the expression of A-beta transporters, which may promote A-beta removal mediated by A-beta transporters.
addition, Klotho's ability to transport A-beta in-body by HCPEpiCs was significantly impaired after Klotho's knock-off.
the neuroplot protection effect of Klotho over-expression, the results of this study suggest that Klotho's potential as a therapeutic target for AD should be further studied.
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