Parkinson's disease(PD)is a neurodegenerative disorder whose core pathological feature is the abnormal accumulation of pathological α-synuclein(α-syn)in the brain,but there are rare clinical therapeutic modalities that target this.As a hot research topic in recent years,meningeal lymphatic vessels(MLVs)play an important role in central nervous system fluid(CNS)drainage,and can promote the exocytosis and clearance of metabolic wastes such as α-syn from the brain.Regulating the morphology and function of MLVs to promote α-syn exocytosis is likely to become an influential direction for future intervention in PD research and provide new approaches for the clinical therapy of PD.In this article,we will overview 3 aspects of the structure and function of MLVs,the role of MLVs in PD,and the strategy of targeting MLVs to treat PD.

Objective This study aimed to investigate the regulatory effect of electroacupuncture(EA)intervention on the protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor 1α(HIF-1α)signaling pathway in the hippocampal tissue of Alzheimer's disease(AD)model mice and its effect on astrocytic glycolytic function,further exploring how EA ameliorates AD-related cognitive impairment.Methods Eighteen APP/PS1 mice were randomly divided into model,EA,and sham EA groups(n=6)using the random number table method.Six wild-type C57BL/6J mice served as the control group.The EA group received EA stimulation at acupoints"Shenshu"(BL23),"Baihui"(GV20),and"Zusanli"(ST36)(administered every other day,20 min per session,for 4 weeks).The sham EA group received identical needle insertions at the same acupoints without electrical stimulation.The control and model groups were only restrained.Cognitive function was assessed using the Morris water maze and Y-maze spontaneous alternation tests.Hippocampal morphology was observed via hematoxylin and eosin staining.Hippocampal β-amyloid peptide 1-42(Aβ1-42)deposition was detected using immunohistochemistry.HIF-1α protein expression,the p-Akt/Akt,and p-mTOR/mTOR ratios were measured using Western blotting.Pyruvate kinase M2(PKM2)and lactate dehydrogenase A(LDHA)activities were quantified using enzyme-linked immunosorbent assay.Hexokinase(HK)activity and L-lactate content were determined using a colorimetric assay.Co-localization of LDHA with the astrocyte marker glial fibrillary acidic protein was quantitatively analyzed using immunofluorescence double-labeling combined with Pearson's correlation coefficient.Results Compared with the control group,the model group mice exhibited cognitive decline,as shown by prolonged escape latency(P<0.01),reduced number of platform crossings,lower time spent in the target quadrant,and decreased spontaneous alternation accuracy(P<0.01).The hippocampal neurons showed cell body swelling,deeper nuclear staining,enlarged intercellular spaces,and increased average optical density of Aβ1-42(P<0.01).The p-Akt/Akt and p-mTOR/mTOR ratios,as well as HIF-1α protein expression,were elevated(P<0.01).PKM2,LDHA,HK,and L-lactic acid levels were significantly increased(P<0.01),and the co-localization coefficient of LDHA with astrocytes was enhanced.Compared to the model group,the EA group of mice showed improved cognitive function.The hippocampal neurons had more intact structures,with a more uniform cell distribution.The average optical density of Aβ1-42 decreased(P<0.01),and the p-Akt/Akt and p-mTOR/mTOR ratios,as well as HIF-1α protein expression,decreased(P<0.01).PKM2,LDHA,HK,and L-lactic acid levels decreased(P<0.05),and the co-localization coefficient of LDHA with astrocytes significantly decreased(P<0.01).No significant improvement was observed in any of the indicators in the sham EA group compared with the EA group.Conclusion EA at"Shenshu"(BL23),"Baihui"(GV20),and"Zusanli"(ST36)ameliorates cognitive dysfunction in AD model mice.The underlying mechanism may involve suppressing the overactivation of the hippocampal Akt/mTOR/HIF-1α signaling pathway,thereby downregulating key glycolytic enzyme activities and reducing abnormal lactate accumulation.Furthermore,the astrocytic glycolytic metabolic pathway may constitute a key therapeutic target for this intervention.

Objective This study aimed to investigate the regulatory effect of electroacupuncture(EA)intervention on the protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor 1α(HIF-1α)signaling pathway in the hippocampal tissue of Alzheimer's disease(AD)model mice and its effect on astrocytic glycolytic function,further exploring how EA ameliorates AD-related cognitive impairment.Methods Eighteen APP/PS1 mice were randomly divided into model,EA,and sham EA groups(n=6)using the random number table method.Six wild-type C57BL/6J mice served as the control group.The EA group received EA stimulation at acupoints"Shenshu"(BL23),"Baihui"(GV20),and"Zusanli"(ST36)(administered every other day,20 min per session,for 4 weeks).The sham EA group received identical needle insertions at the same acupoints without electrical stimulation.The control and model groups were only restrained.Cognitive function was assessed using the Morris water maze and Y-maze spontaneous alternation tests.Hippocampal morphology was observed via hematoxylin and eosin staining.Hippocampal β-amyloid peptide 1-42(Aβ1-42)deposition was detected using immunohistochemistry.HIF-1α protein expression,the p-Akt/Akt,and p-mTOR/mTOR ratios were measured using Western blotting.Pyruvate kinase M2(PKM2)and lactate dehydrogenase A(LDHA)activities were quantified using enzyme-linked immunosorbent assay.Hexokinase(HK)activity and L-lactate content were determined using a colorimetric assay.Co-localization of LDHA with the astrocyte marker glial fibrillary acidic protein was quantitatively analyzed using immunofluorescence double-labeling combined with Pearson's correlation coefficient.Results Compared with the control group,the model group mice exhibited cognitive decline,as shown by prolonged escape latency(P<0.01),reduced number of platform crossings,lower time spent in the target quadrant,and decreased spontaneous alternation accuracy(P<0.01).The hippocampal neurons showed cell body swelling,deeper nuclear staining,enlarged intercellular spaces,and increased average optical density of Aβ1-42(P<0.01).The p-Akt/Akt and p-mTOR/mTOR ratios,as well as HIF-1α protein expression,were elevated(P<0.01).PKM2,LDHA,HK,and L-lactic acid levels were significantly increased(P<0.01),and the co-localization coefficient of LDHA with astrocytes was enhanced.Compared to the model group,the EA group of mice showed improved cognitive function.The hippocampal neurons had more intact structures,with a more uniform cell distribution.The average optical density of Aβ1-42 decreased(P<0.01),and the p-Akt/Akt and p-mTOR/mTOR ratios,as well as HIF-1α protein expression,decreased(P<0.01).PKM2,LDHA,HK,and L-lactic acid levels decreased(P<0.05),and the co-localization coefficient of LDHA with astrocytes significantly decreased(P<0.01).No significant improvement was observed in any of the indicators in the sham EA group compared with the EA group.Conclusion EA at"Shenshu"(BL23),"Baihui"(GV20),and"Zusanli"(ST36)ameliorates cognitive dysfunction in AD model mice.The underlying mechanism may involve suppressing the overactivation of the hippocampal Akt/mTOR/HIF-1α signaling pathway,thereby downregulating key glycolytic enzyme activities and reducing abnormal lactate accumulation.Furthermore,the astrocytic glycolytic metabolic pathway may constitute a key therapeutic target for this intervention.

Parkinson's disease(PD)is a neurodegenerative disorder whose core pathological feature is the abnormal accumulation of pathological α-synuclein(α-syn)in the brain,but there are rare clinical therapeutic modalities that target this.As a hot research topic in recent years,meningeal lymphatic vessels(MLVs)play an important role in central nervous system fluid(CNS)drainage,and can promote the exocytosis and clearance of metabolic wastes such as α-syn from the brain.Regulating the morphology and function of MLVs to promote α-syn exocytosis is likely to become an influential direction for future intervention in PD research and provide new approaches for the clinical therapy of PD.In this article,we will overview 3 aspects of the structure and function of MLVs,the role of MLVs in PD,and the strategy of targeting MLVs to treat PD.