The Study of Golgi Apparatus in Alzheimer’s Disease

Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder leading invariably to death, usually within 7–10 years after diagnosis and is the leading cause of dementia in the elderly. Not only is Alzheimer’s disease a tragic disease in which people suffer from neurodegeneration in the years to come, it also becomes an incredible burden on the public health system. However, there is currently no effective treatment to halt the progression or prevent the onset of Alzheimer’s disease. This is partly due to the fact that the complex pathophysiology of Alzheimer’s disease is not yet completely understood. Recently, Golgi apparatus is found to play an important role in Alzheimer’s disease. In this review, we discuss the changes of Golgi apparatus during clinical progression and pathological development of Alzheimer’s disease. First, changes of Golgi apparatus size in Alzheimer’s disease are summarized. We then address the role of Golgi apparatus in the neuropathology of Alzheimer’s disease. Finally, the role of Golgi apparatus in the pathogenesis of Alzheimer’s disease is discussed. Understanding the contribution of Golgi apparatus dysfunction to Alzheimer’s disease and its pathophysiological basis will significantly impact our ability to develop more effective therapies for Alzheimer’s disease.     

Icariin: A Potential Neuroprotective Agent in Alzheimer’s Disease and Parkinson’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

     

The Emerging Therapeutic Role of NGF in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia that affects the elderly population. Nerve growth factor (NGF) contributes to the survival, regeneration and death of neurons during aging and in neurodegenerative diseases. Recently, research has shown that NGF is related to the pathology, mechanisms and symptoms of AD. Therefore, there is a need to summarize the new advancements in NGF research and its potential therapeutic implications in AD. In this review, we will focus on NGF distribution, production, and function; the interaction of Aβ and NGF; and the effect of different therapy methods on AD. In summary, we hope to describe the experimental and clinical data demonstrating the important roles of NGF for AD treatment.     

Role of RAGE in Alzheimer’s Disease

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer’s disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE–Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.     

The NLRP3 Inflammasome in Alzheimer’s Disease

Innate immunity and inflammatory response plays an important role in the pathogenesis of Alzheimer’s disease (AD). As the major resident immune cells in the brain, microglial cells constantly survey the microenvironment and are activated by and recruited to senile plaques. Subsequently, they can phagocytose amyloid-β (Aβ) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue. Recently, a wealth of information linking the microglia-specific activation of NLRP3 inflammasome to AD pathogenesis has emerged. We review here the activation mechanisms of NLRP3 inflammasome in microglia and several downstream effects in the brain, demonstrating that toxic Aβ peptide can light a fire in NLRP3 inflammasome and eventually induce AD pathology and tissue damage. More importantly, it has been demonstrated that inhibition of NLRP3 could largely protect from memory loss and decrease Aβ deposition in AD transgenic mouse model. So, we further discuss the recent advances and challenges in targeting NLRP3 inflammasome for AD therapy.     

The Convergence of Alzheimer’s Disease Pathogenesis Concepts

Molecular Biology - Advances in the research of molecular factors involved in the onset and progression of Alzheimer’s disease, have led to the creation of several pathogenesis concepts of...     

Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.     

Tetrahydrobiopterin Availability in Parkinson’s and Alzheimer’s Disease; Potential Pathogenic Mechanisms

Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegerative conditions such as Parkinson’s and Alzheimer’s disease.     

The Endocannabinoid System and Alzheimer’s Disease

The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB₁ type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB₂ cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer’s disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.     

Mitochondrial Disorders in Alzheimer’s Disease

Biochemistry (Moscow) - Alzheimer’s disease is the most common age-related neurodegenerative disease. Understanding of its etiology and pathogenesis is constantly expanding. Thus, the...