Apolipoprotein A1, the neglected relative of Apolipoprotein E and its potential role in Alzheimer's disease.
Neural regeneration research
Lipoproteins are multi-molecule assemblies with the primary function of transportation and processing of lipophilic substances within aqueous bodily fluids (blood, cerebrospinal fluid). Nevertheless, they also exert other physiological functions such as immune regulation. In particular, neurons are both sensitive to uncontrolled responses of the immune system and highly dependent on a controlled and sufficient supply of lipids. For this reason, the role of certain lipoproteins and their protein-component (apolipoproteins, Apo's) in neurological diseases is perceivable. ApoE, for example, is well-accepted as one of the major risk factors for sporadic Alzheimer's disease with a protective allele variant (ε2) and a risk-causing allele variant (ε4). ApoA1, the major protein component of high-density lipoproteins, is responsible for transportation of excess cholesterol from peripheral tissues to the liver. The protein is synthesized in the liver and intestine but also can enter the brain via the choroid plexus and thereby might have an impact on brain lipid homeostasis. This review focuses on the role of ApoA1 in Alzheimer's disease and discusses whether its role within this neurodegenerative disorder is specific or represents a general neuroprotective mechanism.
10.4103/1673-5374.310669
Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer's disease: A comprehensive review.
Jin Xin,Guo Jia-Ling,Wang Lin,Zhong Xin,Yao Wei-Fan,Gao Hua,Liu Ming-Yan
European journal of medicinal chemistry
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by neuronal loss and cognitive impairment that harshly affect the elderly individuals. Currently, the available anti-AD pharmacological approaches are purely symptomatic to alleviate AD symptoms, and the curative effects of novel anti-AD drugs focused on Aβ target are disappointing. Hence, there is a tremendous need to adjust AD therapeutic targets and discover novel anti-AD agents. In AD, mitochondrial dysfunction gradually triggers neuronal death from different aspects and worsens the occurrence and progress of AD. Consequently, it has been proposed that the intervention of impaired mitochondria represents an attractive breakthrough point for AD treatments. Due to chemical diversity, poly-pharmacological activities, few adverse effects and multiple targeting, natural products (NPs) have been identified as a valuable treasure for drug discovery and development. Multiple lines of studies have scientifically proven that NPs display ameliorative benefits in AD treatment in relation to mitochondrial dysfunction. This review surveys the complicated implications for mitochondrial dysregulation and AD, and then summarizes the potentials of NPs and their underlying molecular mechanisms against AD via reducing or improving mitochondrial dysfunction. It is expected that this work may open the window to speed up the development of innovative anti-AD drugs originated from NPs and improve upcoming AD therapeutics.
10.1016/j.ejmech.2021.113401
Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease.
Tan Yinyin,Zheng Yanqun,Xu Daiwen,Sun Zhanfang,Yang Huan,Yin Qingqing
Cell & bioscience
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the deposition of extracellular aggregates of amyloid-β (Aβ), the formation of intraneuronal tau neurofibrillary tangles and microglial activation-mediated neuroinflammation. One of the key molecules involved in microglial activation is galectin-3 (Gal-3). In recent years, extensive studies have dissected the mechanisms by which Gal-3 modulates microglial activation, impacting Aβ deposition, in both animal models and human studies. In this review article, we focus on the emerging role of Gal-3 in biology and pathobiology, including its origin, its functions in regulating microglial activation and neuroinflammation, and its emergence as a biomarker in AD and other neurodegenerative diseases. These aspects are important to elucidate the involvement of Gal-3 in AD pathogenesis and may provide novel insights into the use of Gal-3 for AD diagnosis and therapy.
10.1186/s13578-021-00592-7
Alzheimer disease.
Nature reviews. Disease primers
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
10.1038/s41572-021-00269-y
Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer's Disease.
Uddin Md Sahab,Kabir Md Tanvir,Rahman Md Sohanur,Behl Tapan,Jeandet Philippe,Ashraf Ghulam Md,Najda Agnieszka,Bin-Jumah May N,El-Seedi Hesham R,Abdel-Daim Mohamed M
International journal of molecular sciences
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40-42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.
10.3390/ijms21165858
Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives.
Cheng Yuan,Tian Ding-Yuan,Wang Yan-Jiang
Translational neurodegeneration
Alzheimer's disease (AD) is the most common type of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and clearance of Aβ from the brain becomes a main therapeutic strategy for AD. Recent studies found that Aβ clearance in the periphery contributes substantially to reducing Aβ accumulation in the brain. Therefore, understanding the mechanism of how Aβ is cleared in the periphery is important for the development of effective therapies for AD. In this review, we summarized recent findings on the mechanisms of Aβ efflux from the brain to the periphery and discuss where and how the brain-derived Aβ is cleared in the periphery. Based on these findings, we propose future strategies to enhance peripheral Aβ clearance for the prevention and treatment of AD. This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.
10.1186/s40035-020-00195-1
Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Nature
Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
10.1038/s41586-021-03489-0