Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

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.

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Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

10.26434/chemrxiv.14191865.v1 ◽

2021 ◽

Author(s):

Yiran Huang ◽

Liang Sun ◽

Liviu M. Mirica

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluorescence Imaging ◽

Protein Misfolding ◽

Picolinic Acid ◽

Amyloid Β ◽

Fluorescent Sensors ◽

Aβ Oligomers ◽

Turn On ◽

Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

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Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽

10.1017/s1092852900020629 ◽

2007 ◽

Vol 12 (2) ◽

pp. 113-123 ◽

Cited By ~ 15

Author(s):

Daniel D. Christensen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Amyloid Β ◽

Phase Iii ◽

Peroxisome Proliferator ◽

Serious Adverse Events ◽

Amyloid Disease ◽

Aβ Aggregation ◽

Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

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Trichostatin A ameliorates Alzheimer’s disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00746-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Qiang Su ◽

Tian Li ◽

Pei-Feng He ◽

Xue-Chun Lu ◽

Qi Yu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Western Blotting ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Trichostatin A ◽

Amyloid Β ◽

Aβ Oligomers ◽

Aβ Clearance

Abstract Background Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Methods Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. Results TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. Conclusions These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.

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Current Biomarkers for Alzheimer’s Disease: From CSF to Blood

Journal of Personalized Medicine ◽

10.3390/jpm10030085 ◽

2020 ◽

Vol 10 (3) ◽

pp. 85 ◽

Cited By ~ 1

Author(s):

Kun Zou ◽

Mohammad Abdullah ◽

Makoto Michikawa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Early Stage ◽

Biological Fluid ◽

Amyloid Β ◽

Positron Emission Tomography Imaging ◽

Tau Proteins ◽

Csf Biomarkers ◽

Amyloid Β Protein

Alzheimer’s disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, a diagnosis of AD depends on the clinical symptoms of dementia, magnetic resonance imaging to determine brain volume, and positron emission tomography imaging to detect brain amyloid or tau deposition. The best characterized biological fluid markers for AD are decreased levels of amyloid β-protein (Aβ) 42 and increased levels of phosphorylated tau and total tau in cerebrospinal fluid (CSF). However, less invasive and easily detectable biomarkers for the diagnosis of AD, especially at the early stage, are still under development. Here, we provide an overview of various biomarkers identified in CSF and blood for the diagnostics of AD over the last 25 years. CSF biomarkers that reflect the three hallmarks of AD, amyloid deposition, neurofibrillary tangles, and neurodegeneration, are well established. Based on the need to start treatment in asymptomatic people with AD and to screen for AD risk in large numbers of young, healthy individuals, the development of biomarkers for AD is shifting from CSF to blood. Elements of the core pathogenesis of AD in blood, including Aβ42, tau proteins, plasma proteins, or lipids have shown their usefulness and capabilities in AD diagnosis. We also highlight some novel identified blood biomarkers (including Aβ42/Aβ43, p-tau 181, Aβ42/APP669-711, structure of Aβ in blood, and flotillin) for AD.

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Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

Molecular Neurodegeneration ◽

10.1186/s13024-020-00393-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Erik C. B. Johnson ◽

Kaitlyn Ho ◽

Gui-Qiu Yu ◽

Melanie Das ◽

Pascal E. Sanchez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Neurodegenerative Disorder ◽

Epileptiform Activity ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Aβ Oligomers ◽

Behavioral Abnormalities ◽

Amyloid Deposits

Abstract Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.

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Donepezil Derivatives Targeting Amyloid-β Cascade in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205016666190228122956 ◽

2019 ◽

Vol 16 (9) ◽

pp. 772-800 ◽

Cited By ~ 5

Author(s):

Eva Mezeiova ◽

Katarina Chalupova ◽

Eugenie Nepovimova ◽

Lukas Gorecki ◽

Lukas Prchal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Acetylcholinesterase Inhibitor ◽

Amyloid Β ◽

Direct Interaction ◽

Extensive Literature ◽

Aβ Aggregation ◽

Aggregation Inhibition ◽

Approved Drugs

: Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

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Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms22115549 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5549

Author(s):

Tsuyoshi Nakai ◽

Kiyofumi Yamada ◽

Hiroyuki Mizoguchi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mouse Models ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Amyloid Β ◽

Therapeutic Approaches ◽

Age Related ◽

Early Phases

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

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Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211208140551 ◽

2021 ◽

Vol 18 ◽

Author(s):

Rohit Bhatia ◽

Sankha Shubhra Chakrabarti ◽

Upinder Kaur ◽

Gaurav Parashar ◽

Anindita Banerjee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Amyloid Β ◽

Mao B ◽

Clinical Investigations ◽

Aβ Aggregation ◽

Complex Events ◽

Molecular Hybrids

: Alzheimer's disease (AD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cog- nitive domains, including executive function. The progression of AD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AD include a decreased concentration of acetylcholine (ACh), deposi- tion of amyloid-β (Aβ)peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid mole- cules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffolds have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hy- brids as multi-target-directed agents against AD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hy- droxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hy- brids, important clinical investigations and the structure-activity relationship has also been discussed in this compilation.

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Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211035625 ◽

2021 ◽

pp. 0271678X2110356

Author(s):

Min Su Kang ◽

Monica Shin ◽

Julie Ottoy ◽

Arturo Aliaga Aliaga ◽

Sulantha Mathotaarachchi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Fusion Protein ◽

Early Stage ◽

Amyloid Β ◽

Transgenic Rat ◽

Clinical Biomarkers

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer’s disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

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