Targeting Alzheimer's disease with gene and cell therapies

Loera-Valencia, Raúl; Piras, Antonio; Ismail, Muhammad-Al-Mustafa; Manchanda, Shaffi; Eyjolfsdottir, Helga; Saido, Takaomi C.; Johansson, Jan; Eriksdotter, Maria; Winblad, Bengt; Nilsson, Per

doi:10.1111/joim.12759

Cited by 47 publications

(29 citation statements)

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“…While it is unclear how early A673T mutation is needed to provide protection from AD, these mechanistic studies of A673T mutation further validate efforts to reduce the generation and aggregation level of Aβ, the pathological hallmarks of AD, as therapeutic approaches to treat AD. Recently, various stem cells (ESCs, MSCs, NSCs, and iPSCs) therapy and gene therapy for AD have be introduced as a suitable therapeutic source [89][90][91][92][93]. One may expect that A673T mutation would alleviate or even treat AD by inducing A673T mutation of stem cells based on methods such as the CRISPR system and transplanting them into hypothalamus because of suppressed Aβ production.…”

Section: Conclusion: Challenges and Perspectivesmentioning

confidence: 99%

The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer’s Disease

et al. 2021

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Alzheimer's Disease is a progressive neurodegenerative disorder characterized by extracellular amyloid beta peptides, and neuro brillary tangles consisted of intracellular hyperphosphorylated Tau in the hippocampus and cerebral cortex. Most of the mutations in key genes that code for amyloid precursor protein can lead to signi cant accumulation of these peptides in the brain and cause Alzheimer's Disease. Moreover, Some point mutations in amyloid precursor protein can cause familial Alzheimer's Disease, such as Swedish mutation and A673V mutation. However, recent studies have found that the A673T mutation in amyloid precursor protein gene can protect against Alzheimer's Disease, even it is located next to the Swedish mutation and at the same site as A673V mutation, which are pathogenic. It makes us curious about the protective A673T mutation. Here, we summarize the most recent insights of A673T mutation, focus on their roles in protective mechanisms against Alzheimer's Disease, and discuss their involvement in future treatment.

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Section: Conclusion: Challenges and Perspectivesmentioning

confidence: 99%

The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer’s Disease

et al. 2021

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“…In particular, the agent patisiran has just received US Food and Drug Administration approval for treatment of the polyneuropathy caused by hereditary TTR‐mediated amyloidosis in adult patients (Adams et al, ). Gene‐based therapies for AD are likewise also being explored at various other intervention points in the amyloid cascade processes (reviewed in Loera‐Valencia et al, ). The pathways to amyloid clearance in the brain and periphery are summarized in Figure .…”

Section: Pathways To Amyloid Its Clearance and Neuronal Toxicitymentioning

confidence: 99%

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Nalivaeva

Turner

2019

British J Pharmacology

134

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Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…Therefore, it has become more important to generate novel strategies and targets that will effectively alter in any form of the progression and the underlying causes of memory loss in AD. Novel evidence behind alternative mechanisms of the disease and improvements in technology from imaging to gene editing has opened new lines of research that could help to explain the origin and progression of AD [22][23][24][25]. In addition, the field is moving increasingly towards earlier and more accurate diagnostic of the pathology, where technology can help us to better classify and even redefine AD [26].…”

Section: Introductionmentioning

confidence: 99%

Current and emerging avenues for Alzheimer's disease drug targets

et al. 2019

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Loera-Valencia R, Cedazo-Minguez A, ). Current and emerging avenues for Alzheimer's disease drug targets (Review). J Intern Med 2019; 286: 398-437.Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Ab) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Ab and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy. ReviewInsoluble Ab fibrils are taken into consideration as the main responsible for spine pathology. On the other hand, in both transgenic mouse models of AD and human AD brain, synapse defects and memory loss correlate weakly with the presence of Ab Current and novel Alzheimer´s disease therapy targets / R. Loera-Valencia et al.

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Targeting Alzheimer's disease with gene and cell therapies

Cited by 47 publications

References 385 publications

The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer’s Disease

The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer’s Disease

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Current and emerging avenues for Alzheimer's disease drug targets

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