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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is generally accepted that dopamine replacement therapy substantially improves motor symptoms; however, there is a worldwide tendency to include nutrients in treatment strategies. In the present review, caffeine and chocolate are discussed. Caffeine use seems to postpone the occurrence of PD in men, and perhaps also in women who do not take postmenopausal hormone replacement therapy. There are contradictory data concerning possible caffeine-induced improvements in PD symptoms. Given that the basic action of caffeine is the antagonism of adenosine receptors, adenosine antagonists may be a new option for treating PD patients. Furthermore, PD patients tend to have increased chocolate consumption; this may be causally related to ingredients such as phenylethylamine. Thus, nutrients such as caffeine and chocolate may play an important role in postponing and/or improving symptoms in PD. LESS      Full article

Neuroinflammation in amyotrophic lateral sclerosis (ALS) is characterized by activation of monocytes/macrophages and T lymphocytes in the periphery and microglia and astrocytes within the central nervous system. This review emphasizes the role of oxidative stress in promoting systemic inflammation and the early stages of neurodegeneration. Motor axon terminals of ALS patients have significantly increased intraluminal calcium and dysfunctional mitochondria, increasing the formation of lipid peroxides and ferroptosis programmed cell death. Serum lipid peroxides and acute phase proteins are elevated, and regulatory T lymphocytes (Tregs) are dysfunctional, impairing immune-mediated neuroprotection. Macrophages are pro-inflammatory; the expression of genes involved in inflammation is increased in peripheral monocytes/macrophages of ALS patients. Suppressing these multiple components of inflammation is an important therapeutic goal and provides an opportunity to interrupt the self-propagating cytotoxic cycle. Two clinical trials with autologous infusions of ex vivo expanded Tregs have been safe and well tolerated, with promising clinical results associated with suppression of pro-inflammatory lipid peroxides. LESS      Full article

No single animal model can recapitulate all the features of a particular human disease on its own. Historically, rats have been used to study neurobiology and underlying functional networks. Likewise, rat models have been created to study neurodegenerative mechanisms and therapeutic interventions. In the last decades, a shift towards the use of mice has been observed in many research fields, not least because of the comparatively easier genetic manipulation of mice. However, with the full sequence of the rat genome being available, advances in genetic manipulation of the rat, and advanced test regimens and biomarkers at hand, the rat presents itself once more as a valuable model organism for studying neurodegenerative disorders. This review provides an overview of currently available, well-characterized rat models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as their advantages for studying neurodegenerative disorders and evaluating therapeutic interventions. LESS      Full article

Since ferroptosis, a form of cell death characterized by aberrant lipid peroxidation, was proposed 10 years ago, its interaction with the immune system has been revealed gradually. On the one hand, immune cell-secreted cytokines are able to increase or suppress ferroptosis sensitivities of other cell types, such as tumor cells and fibroblasts. On the other hand, ferroptotic cell-released factors have the capacity to modulate the functions of neighboring immune cells, including dendritic cells, macrophages, and T cells. Identifying these immunomodulatory molecules generated during ferroptosis paves the way for developing novel immunotherapy strategies for treating cancer and autoimmune diseases. LESS      Full article

Animal models have great importance in the research of human neurodegenerative diseases due to their value in symptom mimicking, mechanism investigation, and preclinical tests. Although non-human primate and large animal models have good performance in disease modeling due to their high maintenance cost and critical ethical standards, rodent models are commonly used. Rodent models have been successfully applied in modeling many neurological diseases; however, their genetic background, neuroanatomical features, and nervous system development are different from those of humans. Moreover, the short lifespan and small body size of rodent models also limit the monitoring of disease progression and observation of clinical symptoms in studying neuronal disorders that are late-onset or have a long course of progression. In comparison with rodents, rabbits are phylogenetically closer to humans and have closer similarities to humans in brain development, thus are an alternate animal model for human neurological diseases. LESS      Full article

Aim: The associations between dietary macronutrient intake and neurodegenerative diseases (NDDs) have been widely reported; however, the causal effect remains unclear. The current study aimed to estimate the causal relationship between dietary macronutrient intake (i.e., carbohydrate, fat, and protein) and NDDs [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)].Methods: Mendelian randomization (MR) was applied to evaluate the causal relationship between dietary macronutrient intake and NDDs. We used the single-nucleotide polymorphisms strongly associated (P < 5 × 10^-8) with the exposures from the genome-wide association studies as instrumental variables. Inverse-variance weighted, MR-Egger, weighted median, and the MR pleiotropy residual sum and outlier were used to verify the MR assumptions.Results: Genetically predicted higher carbohydrate intake was associated with an increased risk of ALS [odds ratio (OR), 2.741, 95% confidence interval (CI): 1.419-5.293, P = 0.003). Vulnerability to PD was negatively associated with the relative intake of fat (OR, 0.976, 95%CI: 0.959-0.994, P = 0.012) and protein (OR, 0.987, 95%CI: 0.975-1.000, P = 0.042). The study also identified the causal influence of AD on dietary carbohydrate intake (OR, 1.022, 95%CI: 1.011-1.034, P = 0.001).Conclusion: We found solid evidence supporting the idea that a higher carbohydrate proportion causally increases ALS risk. Genetically predicted higher AD risk is causally associated with increased dietary carbohydrate intake. Vulnerability to PD may have a causal relationship with a decrease in the dietary intake of protein and fat. LESS      Full article

Parkinson’s disease (PD), the most common degenerative movement disorder, is clinically manifested with various motor and non-motor symptoms. Degeneration of midbrain substantia nigra pas compacta (SNc) dopaminergic neurons (DANs) is generally attributed to the motor syndrome. The underlying neuronal mechanisms of non-motor syndrome are largely unexplored. Besides SNc, midbrain ventral tegmental area (VTA) DANs also produce and release dopamine and modulate movement, reward, motivation, and memory. Degeneration of VTA DANs also occurs in postmortem brains of PD patients, implying an involvement of VTA DANs in PD-associated non-motor symptoms. However, it remains to be established that there is a distinct segregation of different SNc and VTA DAN subtypes in regulating different motor and non-motor functions, and that different DAN subpopulations are differentially affected by normal ageing or PD. Traditionally, the distinction among different DAN subtypes was mainly based on the location of cell bodies and axon terminals. With the recent advance of single cell RNA sequencing technology, DANs can be readily classified based on unique gene expression profiles. A combination of specific anatomic and molecular markers shows great promise to facilitate the identification of DAN subpopulations corresponding to different behavior modules under normal and disease conditions. In this review, we first summarize the recent progress in characterizing genetically, anatomically, and functionally diverse midbrain DAN subtypes. Then, we provide perspectives on how the preclinical research on the connectivity and functionality of DAN subpopulations improves our current understanding of cell-type and circuit specific mechanisms of the disease, which could be critically informative for designing new mechanistic treatments. LESS      Full article

The role of norepinephrine (NE) in the pathogenesis of Parkinson’s disease (PD) has not been well investigated until recently. The purpose of this perspective article is to review evidence supporting the idea that dysfunction of the locus coeruleus (LC)/NE system in the brain may be fundamentally linked to the pathogenesis of PD. Compelling evidence demonstrates that loss of NE neurons in the LC is sufficient to initiate chronic neuroinflammation, resulting in a progressive and sequential loss of neuronal populations in the brain. This article summarizes the critical role of both microglial and neuronal NADPH oxidase 2 (NOX2), the superoxide and reactive oxygen species generating enzyme, as an important regulator of chronic neuroinflammation. Moreover, NOX2 inhibitors show high efficacy in halting chronic neuroinflammation, oxidative damage, and neurodegeneration in several animal PD models. This line of research offers a promising disease-modifying therapeutic strategy for PD. LESS      Full article

Autophagy is a catabolic mechanism that allows cells to deliver cytoplasmic contents to lysosomes for degradation to maintain energy homeostasis and to protect cells against stress. Autophagy has been directly linked to neurodegeneration and ageing by an extensive body of research. It has become evident that disruption of autophagy contributes significantly to age-related pathologies and to the cognitive and motor declines associated with “healthy” ageing. Autophagic dysfunction causes the accumulation of many of the toxic, aggregate-prone proteins that are responsible for neurodegenerative diseases, including mutant huntingtin, alpha-synuclein, tau, and others. Since upregulation of autophagy has been found to reduce levels of such protein species, the therapeutic potential of autophagy induction as a strategy against age-related diseases and a method for modulating longevity has been widely studied. Here we review the evidence supporting a role for autophagy dysfunction in the progression of the age-associated functional decline in the brain and age-related brain pathologies and discuss the available evidence that upregulation of autophagy may be a valuable therapeutic strategy. LESS      Full article