The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer’s disease (AD).

Background: The association between sarcopenia and mild cognitive impairment (MCI) among elderly adults in China remains unclear. The present study aimed to examine the association based on a nationally representative large‐scale survey.Methods: The study used two waves of data from China Health and Retirement Longitudinal Study (CHARLS) in 2015 and 2018. All subjects met the inclusion criteria were classified based on Asia Working Group for Sarcopenia 2019 criteria. Aging‐associated cognitive decline is used to define MCI, and cognitive function is measured based on four dimensions: orientation, computation, memory, and drawing. OLS and logistic regression model were conducted to analyse the cross‐sectional association between sarcopenia and different cognitive functions. Logistic regression model was conducted to analyse the longitudinal association between sarcopenia and MCI.Results: Totally, 5715 participants aged over 60 years (43.8% women; mean age 67.3 ± 6.0 years) were enrolled in a cross‐sectional association study in 2015, and further 2982 elderly adults were followed up in 2018. During the period, sarcopenia and possible sarcopenia increased from 8.5% to 29.6%. Scores of cognitive and four dimensions (orientation, computation, memory, and drawing) exhibited a decreasing trend from non‐sarcopenia to sarcopenia (P < 0.001). In the fully adjusted OLS regression model, scores of four dimensions were lower in possible sarcopenia and sarcopenia groups when compared with the non‐sarcopenia group (P < 0.05) respectively. The incidence of MCI was 10.1%, 16.5%, and 24.2% for non‐sarcopenia, possible sarcopenia, and sarcopenia groups from 2015 to 2018, with a significantly statistical difference (P < 0.001). Logistic regression model revealed an odds ratio of 1.43 [95% confidence interval (CI): 1.06–1.91, P = 0.017] for the possible sarcopenia group and 1.72 (95% CI: 1.04–2.85, P = 0.035) for sarcopenia group when compared with the non‐sarcopenia group.Conclusions: Sarcopenia is associated with worse cognitive impairment, which provided new evidence for a strong association that warrants further research into mechanistic insights.

China’s population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer’s disease (AD) and related dementias (ADRD). AD’s incidence rate, morbidity, and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals, families and society. The ‘Healthy China Action’ plan of 2019–2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD. This report describes related epidemiological trends, evaluates the economic burden of the disease, outlines current clinical diagnosis and treatment status and delineates existing available public health resources. More specifically, it examines the public health impact of ADRD, including prevalence, mortality, costs, usage of care, and the overall effect on caregivers and society. In addition, this special report presents technical guidance and supports for the prevention and treatment of AD, provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation.

Background: There have been no effective treatments for slowing or reversing Alzheimer’s disease (AD) until now. Growing preclinical evidence, including this study, suggests that mesenchymal stem cells‐secreted exosomes (MSCs‐Exos) have the potential to cure AD. Aims: The first three‐arm, drug‐intervention, phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs‐Exos (ahaMSCs‐Exos) in patients with mild to moderate AD. Methods: The eligible subjects were assigned to one of three dosage groups, intranasally administrated with ahaMSCs‐Exos two times per week for 12 weeks, and underwent follow‐up visits at weeks 16, 24, 36 and 48. Results: No adverse events were reported. In the medium‐dose arm, Alzheimer’s Disease Assessment Scale–Cognitive section (ADAS‐cog) scores decreased by 2.33 (1.19) and the basic version of Montreal Cognitive Assessment scores increased by 2.38 (0.58) at week 12 compared with baseline levels, indicating improved cognitive function. Moreover, the ADAS‐cog scores in the medium‐dose arm decreased continuously by 3.98 points until week 36. There were no significant differences in altered amyloid or tau deposition among the three arms, but hippocampal volume shrank less in the medium‐dose arm to some extent. Conclusions: Intranasal administration of ahaMSCs‐Exos was safe and well tolerated, and a dose of at least 4×10 ⁸ particles could be selected for further clinical trials. Trial registration number: NCT04388982 .

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Although HDAC inhibitors have the ability to ameliorate cognitive impairment, successful treatments in the classic AD animal model are rarely translated into clinical trials. As for the reduction of unwanted side effects, the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed. The review focused on literatures on epigenetic mechanisms in recent years, especially on histone acetylation in terms of the enhancement of specificity, efficacy and avoiding side effects for treating AD.

A major hallmark of Parkinson’s disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra, and the causative mechanism is thought to be the activation of programmed neuronal death. Necroptosis is a regulated process of cell death triggered by RIPK1. Although the pathophysiology of PD has been studied extensively, the cellular mechanism underlying dopaminergic neuron death remains unclear. In this study, we detected a specific miRNA, miR-425, in response to MPTP toxicity and dopaminergic degeneration. In MPTP-treated mice, we observed necroptosis activation and miR-425 deficiency in the substantia nigra, which is correlated with dopaminergic neuron loss. This miRNA targeted RIPK1 transcripts and promoted the phosphorylation of MLKL and necroptosis. Similarly, in the brains of PD patients, miR-425 deficiency and necroptosis activation were also confirmed in dopaminergic neuron. Furthermore, we found that genetic knockdown of miR-425 aggravated MPTP-induced motor deficits and dopaminergic neurodegeneration via early upregulation of necroptotic genes. Intracerebral miR-425 mimics (AgomiR-425) treatment attenuated necroptosis activation and dopaminergic neuron loss, and improved locomotor behaviors. In conclusion, our study suggests that miR-425 deficiency triggers necroptosis of dopaminergic neurons, and targeting miR-425 in MPTP-treated mice restored dysfunctional dopaminergic neurodegeneration and ameliorated behavioral deficits. These findings identify brain delivery of miR-425 as a potential therapeutic approach for the treatment of PD.