Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

Yu, Tien-Wei; Lane, Hsien Yuan; Lin, Chih‐Lang

doi:10.3390/ijms22158208

Cited by 94 publications

(76 citation statements)

References 246 publications

(256 reference statements)

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“…A comprehensive discussion of amyloid-directed AD therapeutics is beyond the scope of this paper; however, recent reviews have provided thorough coverage of this topic ( Bullain and Doody, 2020 ; Avgerinos et al, 2021 ; Decourt et al, 2021 ; Jeremic et al, 2021 ; Lin et al, 2021 ; Restifo, 2021 ; Sun et al, 2021 ; Van Bokhoven et al, 2021 ; Xie et al, 2021 ; Yu et al, 2021 ). Jeremic et al (2021) summarized the late-stage clinical failures of eight secretase inhibitors, and they report on the clinical status of eight amyloid-directed monoclonal antibodies.…”

Section: The Current Status Of Amyloid-targeting Experimental Therape...mentioning

confidence: 99%

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid β (Aβ) peptide, and substantial evidence now implicates soluble, non-fibrillar Aβ oligomers (AβOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aβ and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies – inhibition of the secretase enzymes responsible for Aβ production and clearance of Aβ peptide or amyloid plaques with Aβ-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aβ monomers) were negative, and the crenezumab program (targeting Aβ monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aβ-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AβOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AβOs selectively, and we describe ACU193, the first AβO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AβO hypothesis of AD.

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Section: The Current Status Of Amyloid-targeting Experimental Therape...mentioning

confidence: 99%

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

et al. 2022

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“…Although in animal studies Epothilone D rescued working and spatial memory deficits in aged tau transgenic mice (reviewed in Yu et al, 2021), this drug was discontinued following a Phase 1 clinical study in 2013, with no information regarding drug's effectiveness and side effects in humans (Bristol-Myers Squibb, 2013). 2.…”

Section: Microtubule Stabilizersmentioning

confidence: 99%

“…The clinical trials performed in humans with tauopathies had no positive outcome (Ivashko-Pachima and Gozes, 2021). In a phase II double-blind randomized controlled trial, NAP showed cognitive and functional improvement in mild cognitive impairment (MCI) patients, after a 12-week intranasal NAP administration (reviewed by Yu et al (2021). By the time this review is being written, clinical trials on MCI, progressive supranuclear palsy and schizophrenia have all been discontinued, and the one for frontotemporal dementia is inactive (as per alzforum webpage 20.09.2021).…”

Section: Microtubule Stabilizersmentioning

confidence: 99%

Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia

Santiago-Mujika

Lüthi-Carter

Giorgini

et al. 2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia in older people. Although these two dementia types differ in their etiology, they share many pathophysiological and morphological features, including neuronal loss, which is associated with the microtubule (MT) destabilization. Stabilization of MTs is achieved in different ways: through interactions with MT binding proteins (MTBP) or by posttranslational modifications (PTMs) of tubulin. Polyglutamylation and tyrosination are two foremost PTMs that regulate the interaction between MTs and MTBPs, and play, therefore, a role in neurodegeneration. In this review, we summarize key information on tubulin PTMs in relation to AD and VaD and address the importance of studying further the tubulin code to reveal sites of potential intervention in development of novel and effective dementia therapy.

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“…In recent years, clinical trials of several drugs targeting Aβ, such as BACE1 inhibitors and anti-Aβ monocolonal antibodies, have failed, implicating the importance of targeting pathologies other than Aβ. Thus, more attention has been paid to drug candidates acting on other targets, including tau and neuroinflammation [ 10 ]. However, the Aβ oligomer hypothesis is still considered to be valid, and AβOs are attractive targets for the development of therapeutic candidates.…”

Section: Introductionmentioning

confidence: 99%

Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Araki

Kametani

2022

Antioxidants

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Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

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Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

Cited by 94 publications

References 246 publications

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia

Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

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