scholarly journals BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease

2019 ◽  
Vol 12 (1) ◽  
pp. 41 ◽  
Author(s):  
Miguel Maia ◽  
Emília Sousa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Health Concern ◽  
Pharmacological Agents ◽  
Drug Candidates ◽  
Structure Activity ◽  
Β Amyloid ◽  
Cns Penetration ◽  
Disease Modifying Agents ◽  
Bace 1

Alzheimer’s disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia. Hence, several research and development (R&D) programs have been led by the pharmaceutical industry in an effort to discover effective and safety anti-amyloid agents as disease modifying agents for AD. Among 19 drug candidates identified in the AD pipeline, nine have their mechanism of action centered in the activity of β or γ-secretase proteases, covering almost 50% of the identified agents. These drug candidates must fulfill the general rigid prerequisites for a drug aimed for central nervous system (CNS) penetration and selectivity toward different aspartyl proteases. This review presents the classes of γ-secretase and beta-site APP cleaving enzyme 1 (BACE-1) inhibitors under development, highlighting their structure-activity relationship, among other physical-chemistry aspects important for the successful development of new anti-AD pharmacological agents.

Alzheimer's Disease: Related Targets, Synthesis of Available Drugs, Bioactive Compounds Under Development, and Promising Results Obtained from Multi-target Approaches

2020 ◽  
Vol 21 ◽  
Author(s):  
Natália F. F. Pirolla ◽  
Victor S. Batista ◽  
Flávia Pereira Dias Viegas ◽  
Vanessa Silva Gontijo ◽  
Caitlin R. McCarthy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bioactive Compounds ◽  
Medicinal Chemistry ◽  
Therapeutic Targets ◽  
Effective Drug ◽  
Research Projects ◽  
Drug Candidates ◽  
Structure Activity ◽  
Synthetic Routes

We describe herein the therapeutic targets involved in Alzheimer's disease as well as the available drugs and their synthetic routes. Bioactive compounds under development are also exploited to illustrate some recent research ad-vances on the medicinal chemistry of Alzheimer's disease, including structure-activity relationships for some targets. The importance of multi-target approaches, including some examples from our research projects, guides new perspectives in the search of more effective drug candidates. This review comprises the period between 2001 and early 2020.

scholarly journals BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

2015 ◽  
Vol 36 (7) ◽  
pp. 1281-1294 ◽  
Author(s):  
Kavi Devraj ◽  
Slobodan Poznanovic ◽  
Christoph Spahn ◽  
Gerhard Schwall ◽  
Patrick N Harter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Bace 1

Endothelial cells of the blood–brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood–brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer’s disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood–brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D- dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer’s disease mouse model we show that BACE-1 is upregulated at the blood–brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood–brain barrier in β-amyloid generation and in vascular aspects of Alzheimer’s disease, particularly in the development of cerebral amyloid angiopathy.

scholarly journals Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

2021 ◽  
Vol 14 ◽  
Author(s):  
Pei-Pei Guan ◽  
Long-Long Cao ◽  
Yi Yang ◽  
Pu Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Calcium Ions ◽  
Neuronal Networks ◽  
Molecular Mechanisms ◽  
Amyloid Protein ◽  
Drug Candidates ◽  
Current Review ◽  
Β Amyloid

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by the production and deposition of β-amyloid protein (Aβ) and hyperphosphorylated tau, leading to the formation of β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Although calcium ions (Ca2+) promote the formation of APs and NFTs, no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD has been published. Therefore, the current review aimed to fill the gaps between elevated Ca2+ levels and the pathogenesis of AD. Specifically, we mainly focus on the molecular mechanisms by which Ca2+ affects the neuronal networks of neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy. Furthermore, the roles of Ca2+ transporters located in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosome in mediating the effects of Ca2+ on activating neuronal networks that ultimately contribute to the development and progression of AD are discussed. Finally, the drug candidates derived from herbs used as food or seasoning in Chinese daily life are summarized to provide a theoretical basis for improving the clinical treatment of AD.

Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer’s Disease

2021 ◽  
Vol 28 ◽  
Author(s):  
Bhupinder Kumar ◽  
Amandeep Thakur ◽  
Ashish Ranjan Dwivedi ◽  
Rakesh Kumar ◽  
Vinod Kumar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Strategies ◽  
Design Strategies ◽  
Drug Candidates ◽  
Esterase Inhibitors ◽  
Current Review ◽  
Single Target ◽  
Symptomatic Management ◽  
Β Amyloid

Abstract: Alzheimer’s disease (AD) is a complex neurological disorder, and multiple pathological factors are believed to be involved in the genesis and progression of the disease. A number of hypotheses, including Acetylcholinesterase, Monoamine oxidase, β-Amyloid, Tau protein, etc., have been proposed for the initiation and progression of the disease. At present, acetylcholine esterase inhibitors and memantine (NMDAR antagonist) are the only approved therapies for the symptomatic management of AD. Most of these single-target drugs have miserably failed in the treatment or halting the progression of the disease. Multi-factorial diseases like AD require complex treatment strategies that involve simultaneous modulation of a network of interacting targets. Since the last few years, Multi-Target-Directed Ligands (MTDLs) strategy, drugs that can simultaneously hit multiple targets, is being explored as an effective therapeutic approach for the treatment of AD. In the current review article, the authors have briefly described various pathogenic pathways associated with AD. The importance of Multi-Target-Directed Ligands and their design strategies in recently reported articles have been discussed in detail. Potent leads are identified through various structure-activity relationship studies, and their drug-like characteristics are described. Recently developed promising compounds have been summarized in the article. Some of these MTDLs with balanced activity profiles against different targets have the potential to be developed as drug candidates for the treatment of AD.

scholarly journals Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

2018 ◽  
Vol 1 (3) ◽  
pp. e00015 ◽  
Author(s):  
S.O. Bachurin ◽  
E.V. Bovina ◽  
A.A. Ustyugov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Neuronal Loss ◽  
Phase Iii ◽  
Molecular Pathways ◽  
Drug Candidates ◽  
Neurodegenerative Process ◽  
Thomson Reuters ◽  
Disease Modifying Agents

Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites www.clinicaltrials.gov and Alzforum.org as well as the Thomson Reuters «Integrity» database. We revealed three major trends in AD drug discovery. First, developing of “disease-modifying agents” could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.

scholarly journals Alternative pathways for production of β-amyloid peptides of Alzheimer's disease

2008 ◽  
Vol 389 (8) ◽  
Author(s):  
Vivian Hook ◽  
Israel Schechter ◽  
Hans-Ulrich Demuth ◽  
Gregory Hook
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Posttranslational Modifications ◽  
Cathepsin B ◽  
Cathepsin D ◽  
General Meeting ◽  
Glutaminyl Cyclase ◽  
Alternative Pathways ◽  
Β Amyloid ◽  
Bace 1

Abstract This highlight article describes three Alzheimer's disease (AD) studies presented at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic β-amyloid (Aβ) peptides. One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) β-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the WT β-secretase site, they suggested continuing the search for additional β-secretase(s). The second group reported cathepsin B as an alternative β-secretase possessing excellent kinetic efficiency and specificity for the WT β-secretase site. Significantly, inhibitors of cathepsin B improved memory, with reduced amyloid plaques and decreased Aβ(40/42) in brains of AD animal models expressing amyloid precursor protein containing the WT β-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Aβ. Results showed that cathepsin B, but not BACE 1, efficiently cleaves the WT β-secretase isoaspartate site. Furthermore, cyclization of N-terminal Glu by glutaminyl cyclase generates highly amyloidogenic pGluAβ(3–40/42). These presentations suggest cathepsin B and glutaminyl cyclase as potential new AD therapeutic targets.

Аnticholinesterase and antioxidant activity of new binary conjugates of (с)-carbolines

2019 ◽  
Vol 484 (1) ◽  
pp. 104-108
Author(s):  
G. F. Makhaeva ◽  
E. F. Shevtsova ◽  
N. P. Boltneva ◽  
N. V. Kovaleva ◽  
E. V. Rudakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Activity ◽  
Anticholinesterase Activity ◽  
Amyloid Aggregation ◽  
Varying Length ◽  
Β Amyloid ◽  
New Compounds

This study presents the synthesis of binary tetrohydro-γ-carbolines with ditriazol spacers of varying length, which exhibit anticholinesterase and antioxidant activity, as compared to the original Dimebon prototype. Anticholinesterase activity suggests the potential ability of the new compounds to block β-amyloid aggregation induced by anticholinesterase, making them promising candidates for further research preparations for the treatment of Alzheimer's disease. Particular attention should be paid to the conjugate with an intertriazol hexamethylene spacer, which can be regarded as the leading compound in this series.

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