Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.

Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases.

Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.

Aim: The atherogenic index of plasma (AIP) was significantly related to adverse outcomes in patients with cardiovascular disease. Our aim was to investigate the association between AIP and adverse outcomes in acute ischemic stroke.Methods: Patients with acute ischemic stroke (AIS) admitted between 2015 and 2018 were prospectively enrolled in this study. Functional outcomes were evaluated by the modified Rankin Scale (mRS). Poor outcomes were defined as mRS 3–6. The relationship of AIP with the risk of outcomes was analyzed by multivariate logistic regression models.Results: A total of 1,463 patients with AIS within 24 h of symptom onset were enrolled. The poor outcome group had a significantly higher level of AIP [0.09 (−0.10 to 0.27) vs. 0.04 (−0.09 to 0.18), p < 0.001] compared with the good outcome group. Multivariable logistic regression analysis showed that higher AIP was associated with poor outcomes in all the stroke patients (OR 1.84, 95% CI, 1.23–2.53, p = 0.007), which was more evident in patients with large-artery atherosclerosis subtype (OR 1.90, 95% CI, 1.53–2.62, p = 0.002), but not in the other subtypes. Receiver operating curve (ROC) analysis revealed that the best predictive cutoff value of AIP was 0.112, with a sensitivity of 70.8% and a specificity of 59.2%, and the area under the ROC curves for AIP was 0.685.Conclusion: AIP may be an important and independent predictor of the outcome of dysfunction in patients with AIS, especially the stroke subtype of large-artery atherosclerosis.