Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges DOI

Pauline Zipfel,

Christophe Rochais, Kévin Baranger

et al.

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(19), P. 10705 - 10725

Published: May 27, 2020

Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence their pathological roles have also been obtained last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries involvement central nervous system (CNS) disorders, and particular Alzheimer's disease (AD), paved way to consider MMP modulators as promising strategies. Over past few diverse approaches undertaken design agents targeting various purposes, leading, more recently, encouraging developments. In this article, we will present recent examples inhibitors ranging from small molecules peptidomimetics biologics. We discuss scientific knowledge that has led development emerging tools techniques overcome challenges selective inhibition.

Language: Английский

PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis DOI Open Access
Chiara Fedeli, Riccardo Filadi, Alice Rossi

et al.

Autophagy, Journal Year: 2019, Volume and Issue: 15(12), P. 2044 - 2062

Published: March 20, 2019

PSEN2 (presenilin 2) is one of the 3 proteins that, when mutated, causes early onset familial Alzheimer disease (FAD) cases. In addition to its well-known role within γ-secretase complex (the enzyme ultimately responsible for Aβ peptides formation), endowed with some γ-secretase-independent functions in distinct cell signaling pathways, such as modulation intracellular Ca

Language: Английский

Citations

105
APP/Aβ structural diversity and Alzheimer's disease pathogenesis DOI Creative Commons

Alex E. Roher,

Tyler A. Kokjohn,

Steven Clarke

et al.

Neurochemistry International, Journal Year: 2017, Volume and Issue: 110, P. 1 - 13

Published: Aug. 14, 2017

Language: Английский

Citations

94
Scopolamine, a Toxin-Induced Experimental Model, Used for Research in Alzheimer’s Disease DOI
Win Ning Chen, Keng Yoon Yeong

CNS & Neurological Disorders - Drug Targets, Journal Year: 2020, Volume and Issue: 19(2), P. 85 - 93

Published: Feb. 14, 2020

Scopolamine as a drug is often used to treat motion sickness. Derivatives of scopolamine have also found applications antispasmodic drugs among others. In neuroscience-related research, it induce cognitive disorders in experimental models readily permeates the bloodbrain barrier. context Alzheimer’s disease, its effects include causing cholinergic dysfunction and increasing amyloid-β deposition, both which are hallmarks disease. Hence, application disease research proven pivotal but seldom discussed. this review, relationship between will be delineated through an overall effect administration specific mechanisms action, discussing mainly influences on function amyloid cascade. The validity model impairment or neurotoxin discussed terms advantages limitations with future insights.

Language: Английский

Citations

90
Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease DOI Creative Commons
Daniela Liccardo, Federica Marzano, Federica Carraturo

et al.

Frontiers in Physiology, Journal Year: 2020, Volume and Issue: 11

Published: July 3, 2020

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly population, representing a global public health priority. Despite large improvement understanding pathogenesis AD, etiology this disorder remains still unclear, and no current treatment able to prevent, slow, or stop its progression. Thus, there keen interest identification modification risk factors novel molecular mechanisms associated with development progression AD. In context, it worth noting that several findings support existence direct link between neuronal non-neuronal inflammation/infection AD Importantly, recent studies are now supporting relationship periodontitis, chronic inflammatory oral disease, The underlying association remain be fully elucidated, however, generally accepted, although not confirmed, pathogens can penetrate bloodstream, inducing low-grade systemic inflammation negatively affects brain function. Indeed, report demonstrated their toxic proteins infect patients. For instance, when progresses from early more advanced stages, patients could longer adequately adhere proper hygiene practices, thus leading dysbiosis that, turn, fuels infection, such as periodontitis. Therefore, review, we will provide an update on emerging (preclinical clinical) evidence supports existing periodontitis More detail, discuss data attesting share common similar hyper-inflammatory phenotype.

Language: Английский

Citations

89
Functions of amyloid precursor protein in metabolic diseases DOI
Yanjun Guo, Qinqiu Wang, Shenghui Chen

et al.

Metabolism, Journal Year: 2020, Volume and Issue: 115, P. 154454 - 154454

Published: Nov. 26, 2020

Language: Английский

Citations

74
Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders DOI Creative Commons

Gregory Hook,

Thomas Reinheckel, Junjun Ni

et al.

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(3), P. 600 - 629

Published: June 16, 2022

Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion the resulted significant improvements behavioral deficits, neuropathology, and/or biomarkers traumatic injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), periodontitis AD models as shown 12 studies. One study found beneficial effects double cathepsin S KO mice multiple sclerosis model. Transgenic using amyloid precursor protein (APP) mimicking common sporadic three studies showed that improved memory, biomarkers; two used APP representing rare familial no effect, highly engineered constructs reported slight increases biomarker. In clinical studies, all reports CTSB enzyme was upregulated diverse disorders, including which elevated positively correlated with cognitive dysfunction. wide range models, also not downregulated. Further, human genetic mutation data provided precedence upregulation causing disease. Thus, consilience results dysfunction reduced pathology through blockade causes phenotypes. The overall findings provide strong support rational drug target inhibitors therapeutic candidates disorders.

Significance Statement

provides comprehensive compilation extensive on deleting (CTSB) neurological mouse Mice lacking display neurobehavioral neuronal cell death biomarkers. significance compelling evidence validates discovery potential therapeutics treating numerous diseases.

Language: Английский

Citations

64
Synaptic dysfunction in early phases of Alzheimer's Disease DOI
Silvia Pelucchi, Fabrizio Gardoni, Mónica Di Luca

et al.

Handbook of clinical neurology, Journal Year: 2022, Volume and Issue: unknown, P. 417 - 438

Published: Jan. 1, 2022

Language: Английский

Citations

58
Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer’s disease and normal physiology DOI Creative Commons
Grant Pfundstein, Alexander G. Nikonenko, Vladimir Sytnyk

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: July 26, 2022

Alzheimer's disease (AD) is an incurable neurodegenerative disorder in which dysfunction and loss of synapses neurons lead to cognitive impairment death. Accumulation aggregation neurotoxic amyloid-β (Aβ) peptides generated via amyloidogenic processing amyloid precursor protein (APP) considered play a central role the etiology. APP interacts with cell adhesion molecules, influence normal physiological functions APP, its non-amyloidogenic processing, formation Aβ aggregates. These surface glycoproteins also mediate attachment neuronal induce intracellular signaling contributing toxicity. In this review, we discuss current knowledge surrounding interactions molecules analyze evidence critical these proteins regulating function as well This necessary piece complex AD puzzle, should understand order develop safe effective therapeutic interventions for AD.

Language: Английский

Citations

48
Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy DOI Creative Commons
Meina Quan, Shuman Cao, Qi Wang

et al.

Phenomics, Journal Year: 2023, Volume and Issue: 3(4), P. 333 - 349

Published: April 3, 2023

Abstract Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease (AD). In addition to mutations three main causative genes familial AD (FAD) including presenilins amyloid precursor protein genes, studies have identified several as most plausible for onset progression FAD, such triggering receptor expressed myeloid cells 2 , sortilin-related 1 adenosine triphosphate-binding cassette transporter subfamily A member 7 . The apolipoprotein E ε4 allele is reported be strongest risk factor sporadic (SAD), it also plays an important role FAD. Here, we reviewed recent developments that contributed understanding phenotypes FAD compared them with SAD. We further advancements gene therapy discussed future perspectives based phenotypes.

Language: Английский

Citations

33
Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease DOI
George A. Pantelopulos, Conor B. Abraham, John E. Straub

et al.

Annual Review of Biophysics, Journal Year: 2024, Volume and Issue: 53(1), P. 455 - 486

Published: Feb. 21, 2024

Cholesterol has been conjectured to be a modulator of the amyloid cascade, mechanism that produces amyloid-β (Aβ) peptides implicated in onset Alzheimer's disease. We propose cholesterol impacts genesis Aβ not through direct interaction with proteins bilayer, but indirectly by inducing liquid-ordered phase and accompanying liquid-liquid separations, which partition cascade different lipid domains ultimately endocytotic pathways. explore full process context phases induced cholesterol, including protein partitioning into domains, mechanisms endocytosis experienced secretases, pH-controlled activation precursor secretases specific environments. Outstanding questions on essential role are identified for future studies.

Language: Английский

Citations

10