Tau Protein-Targeted Therapies in Alzheimer’s Disease: Current State and Future Perspectives

Pluta, Ryszard; Ułamek-Kozioł, Marzena

doi:10.36255/exonpublications.alzheimersdisease.2020.ch4

Cited by 16 publications

(8 citation statements)

References 57 publications

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“…Accumulation of tau tangles strongly correlates with cognitive impairment and neurodegeneration in AD, and this recognition has stimulated a shift toward the development of tau-targeting therapies [4]. Although tau-targeting therapies hold great promise, to date only a few have made it to clinical trials [5].…”

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confidence: 99%

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Latimer

Liachko

2021

GeroScience

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Alzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

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confidence: 99%

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Latimer

Liachko

2021

GeroScience

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“…Regardless of the observed statistical heterogeneity, and when the evidence was available (at least two included RCTs in one subgroup), we conducted the following prespecified subgroup analyses: drugs blocking tau pathology which is characterized by abnormal tau aggregates [15][16][17] (targeting tau post-translational modifications prior to pathological tau aggregation, inhibiting tau aggregation directly, immunotherapy enhancing tau protein clearance, and stabilization of microtubules which improve symptoms of taupathies); tau phosphorylation inhibition categorized by relevant kinase inhibitors 16 (glycogen synthase kinase-3b [GSK-3b] inhibitors, Fyn tyrosine kinase inhibitors, c-Abl tyrosine kinase inhibitors, and multidomain inhibitors); herbal medicine or its extracts 18 (curcumin, resveratrol, rosmarinic acid, sodium oligomannate); clinical phase (phase II and phase III); and length of follow-up(<24 weeks and ≥24 weeks).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and safety of anti‐tau drugs for Alzheimer's disease: Systematic review and meta‐analysis

Zheng

Tang

Yang

et al. 2022

J American Geriatrics Society

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Objective To assess the cognitive effectiveness and safety of tau‐targeting drugs for Alzheimer's disease (AD) Methods The MEDLINE, Embase, Cochrane Library, PsycINFO, http://clinicaltrials.gov, and WHO International Clinical Trials Registry Platform databases were searched from inception to 22 November 2021. A systematic review and meta‐analysis of randomized controlled trials were performed Results Thirty‐four randomized controlled trials comprising 5549 participants, of which fifteen (51.7%) had a low risk of bias, were included. The meta‐analysis showed no differences in the cognitive subscale of the AD: Assessment Scale (ADAS‐Cog) between anti‐tau drugs and placebo (mean difference [MD]: −0.77, 95% CI: −1.64 to 0.10; minimal important difference 3.1–3.8 points, moderate certainty evidence). For ADAS‐Cog, the results subgroup analysis suggested a statistical effect of tau posttranslational modifications on drug inhibition (MD: −0.80, 95% CI: −1.43 to −0.17), which was not seen with tau aggregation inhibitors or immunotherapy (interaction p = 0.24). A total of 11.0%, 5.2%, and 4.8% of drugs inhibiting tau aggregation, immunotherapy, and drugs targeting posttranslational modifications, respectively, had a reduced risk of dropouts due to adverse events (AEs). Discussion Current evidence suggests that anti‐tau drugs are unlikely to have an important impact on slowing cognitive impairment. Although the subgroup analysis suggested that inhibition of tau posttranslational modifications is statistically effective and generally safer because of reduced dropouts due to AEs, the analysis has limited credibility. Additional large‐scale and well‐designed randomized and placebo‐controlled trials will be necessary to explore the benefit of a certain type of anti‐tau drug for AD.

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“…Future studies are warranted to help elucidate the exact mechanism of this interaction. The mechanisms underlying the current AD therapy [ 315 , 316 , 317 ], which target these abnormal proteins, can be connected to the ability to rescue impairment of structural plasticity in the hippocampus with AD. Future understanding of molecular mechanisms responsible for this interplay may expose novel therapeutic targets as well as increase the effectiveness of existing anti-HPtau and Aβ therapies.…”

Section: Hippocampal Structural Plasticity In Neurodegenerative Diseasesmentioning

confidence: 99%

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

Weerasinghe-Mudiyanselage

Ang

Kang

et al. 2022

IJMS

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Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.

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Tau Protein-Targeted Therapies in Alzheimer’s Disease: Current State and Future Perspectives

Cited by 16 publications

References 57 publications

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Effectiveness and safety of anti‐tau drugs for Alzheimer's disease: Systematic review and meta‐analysis

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

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