New target path for Alzheimer's disease - Drp1-HK1-NLRP3

Alzheimer's disease (AD) is an age-related neurodegenerative disease associated with the deposition of amyloid β protein plaques and tau protein tangles in the brain, accompanied by the death of aggressive nerve cells.
although there has been decades of progress in understanding the pathogenesis of AD, the mechanisms that lead to AD-related cell damage and cognitive impairment remain unclear.
recently, researchers at Case Western Reserve University School of Medicine discovered a new target path path for AD progression, Drp1-HK1-NLRP3, which will help develop treatments for early intervention in neurodegenerative diseases.
results were published in Science Advances on December 4.
" detection of the disease and its treatment at an early stage is critical to our fight against its devastating effects.
new paths discovered by Professor Xin Qi's lab can be targeted before the disease develops to the point where it causes cognitive problems.
A. Pieper, one of the authors of the study and director of the Center for Neurotherapy at the Harrington Discovery Institute.
: Science Advances showed clear signs of whiteness loss and demyelination before plaques and tangles became apparent in AD patients, usually early in the course of the disease, and predicted disease status.
brain damage can be attributed to damage to the central nervous system's less protrusive glial cells (oligodendrocyte, OL) and myelin-forming glial cells.
loss of OL, decreased myelin density, axon loss, and asstary glial cell growth are the major white matter changes that occur in the brains of AD patients and animals.
, OL damage and white degeneration are considered to be the main events in AD pathology in the event of failure of anti-amyloid therapy.
that since OL injury is a prerequisite for demyelination and white degeneration, the researchers first evaluated THEL changes in AD.
they found that mature OL experienced inflammatory damage mediated by the NLRP3-dependent Gasdermin D (GSDMD) in both AD patients (figure A-D below) and AD mouse models (E-K below), accompanied by demyelination and axis mutation.
mature OL experiences GSDMD-related inflammatory damage.
(Source: Science Advances) In addition, the team previously reported that the overactivation of the systemic suppression of the power-related protein 1 (Drp1; mitochondrial split bird glycoside triphosphase) reduced mature OL death and demyelination in animal models with multiple sclerosis.
, in this study, they tested the status of Drp1 in the AD model OL and found that Drp1-mediated mitochondrial division was over-activated in the brains of AD patients, whiteness in AD mice, and mature OL exposed to toxic A-beta peptides.
and mature OL-specific knock-off Drp1 eliminates NLRP3 inflammatory small body activation, corrects myelin loss (Figure E, F below), and improves cognitive abilities in AD mice (Figure J, K below).
Source: Science Advances Further mechanism studies have shown that excessive activation of Drp1 in mature OL induces glycolysis defects in the AD model by inhibiting hesitose kinase 1 (HK1; a mitochondrial enzyme that initiates glycolysis), thereby triggering NLRP3-related inflammation.
overall, this study demonstrates the importance of OL glycolysis defects in AD progression and emphasizes that the activation of the Drp1-HK1-NLRP3 signal axis is an important mechanism and therapeutic target for AD whiteness degeneration.
: In a healthy state, HK1 locates the outer membrane of the mitochondrial to bind to VDAC.
mitochondrial HK1 converts glucose into glucose-6-phosphoric acid (G-6-Pi) through phosphation, initiating glycolysis to produce acetone and lactic acid as energy sources.
can also enter neurons to support TCA circulation and neuron survival.
right: In AD, Drp1 in mature OL is overactive due to stress (e.g., soluble A-beta).
over-activated Drp1 is transported to mitochondrials, where it prioritizes the binding of VDAC, separating HK1 from VDAC.
this separation inseptifics HK1 and inhibits glycolysis.
HK1 inactivation and glycolysis inhibition lead to glycolysis stress, inducing inflammatory damage of NLRP3 inflammatory small body activation, GSDMD and pro-IL-1 beta cleavage and mature OL.
result is demyelination and shaft mutation.
drp1 in mature OL prevented these abnormal events from occurring from the outset, thereby reducing OL inflammation, myelin loss, and white matter degeneration observed in AD.
Xin Qi's lab, which led the study, has been studying Drp for a decade, focusing on Parkinson's disease and Huntington's disease.
" he said: "The results of this study suggest that targeting the Drp1-HK1-NLRP3 pathline and reducing the expression of the Drp1 protein can help reduce the downstream cascading effect of abnormal brain function associated with AD progression.
" in fact, Professor Qi's lab has patented a small molecule of a peptide inhibitor that regulates the expression of Drp1, which prevents the degeneration of brain cells.
, Pieper said, only a handful of drugs have been approved for AD since AD was discovered in 1907.
these drugs provide short-term symptom relief benefits by enhancing nerve delivery, they do not slow the progression of the disease.
the scale of AD is exploding as the population ages, it is critical to identify early treatments for AD.
resources: 1 s New pathway in Alzheimer's disease providess earlier target for potential therapies (Source: Medical Press) 2 s Xinwen Zhang et al. Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer's disease. Science Advances (2020). DOI: 10.1126/sciadv.abb8680。