-
1.
A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer's Disease.
Mukhopadhyay, S, Banerjee, D
Journal of Alzheimer's disease : JAD. 2021;(4):1537-1552
Abstract
Alzheimer's disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a Clinico-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of 'amyloid cascade hypothesis' itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidative stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.
-
2.
Moving fluid biomarkers for Alzheimer's disease from research tools to routine clinical diagnostics.
Zetterberg, H, Blennow, K
Molecular neurodegeneration. 2021;(1):10
Abstract
Four fluid-based biomarkers have been developed into diagnostic tests for Alzheimer's disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology; total-tau and phosphorylated tau, markers of AD-related changes in tau metabolism and secretion; and neurofilament light, a marker of neurodegeneration. When measured in cerebrospinal fluid, these biomarkers can be used in clinical practice to support a diagnosis of mild cognitive impairment or dementia due to AD. Recently, technological breakthroughs have made it possible to measure them in standard blood samples as well. Here, we give an updated account of the current state of the fluid-based AD biomarker research field. We discuss how the new blood tests may be used in research and clinical practice, and what role they may play in relation to more established diagnostic tests, such as CSF biomarkers and amyloid and tau positron emission tomography, to facilitate the effective implementation of future disease-modifying therapies.
-
3.
Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β.
Chai, AB, Lam, HHJ, Kockx, M, Gelissen, IC
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(9):158980
Abstract
Since the identification of the apolipoprotein E (apoE) *ε4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-β (Aβ) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic Aβ peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the Aβ processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired Aβ clearance, however data regarding Aβ synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with Aβ. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform.
-
4.
Molecular Imaging of Fluorinated Probes for Tau Protein and Amyloid-β Detection.
Yeo, SK, Shepelytskyi, Y, Grynko, V, Albert, MS
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Alzheimer's disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-β (Aβ). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aβ can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aβ. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored.
-
5.
Inflammation: A Major Target for Compounds to Control Alzheimer's Disease.
Maccioni, RB, Navarrete, LP, González, A, González-Canacer, A, Guzmán-Martínez, L, Cortés, N
Journal of Alzheimer's disease : JAD. 2020;(4):1199-1213
Abstract
Several hypotheses have been postulated to explain how Alzheimer's disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer's disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer's disease treatment.
-
6.
Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer's disease?
Maitre, M, Klein, C, Patte-Mensah, C, Mensah-Nyagan, AG
Progress in neurobiology. 2020;:101800
Abstract
Among several processes, a decrease in amyloid-beta (Aβ) peptide elimination is thought to be one of the major pathophysiological factors in Alzheimer's disease (AD). Neprilysin (NEP) is a key metalloproteinase controlling the degradation and clearance of Aβ peptides in the brain. NEP is induced by several pharmacological substances, amyloid deposits and somatostatin, but the physiological regulation of its expression remains unclear. This situation hampers the exploitation of NEP regulatory factors/mechanisms to develop effective strategies against Aβ peptide accumulation-induced brain toxicity. Based on recent data aimed at elucidating this major question, the present paper addresses and critically discusses the role of 5-hydroxyindole-acetic acid (5-HIAA) and kynurenic acid (KYNA) in the regulation of NEP activity/expression in the brain. Both 5-HIAA and KYNA are endogenous metabolites of tryptophan, an essential amino-acid obtained through diet and gut microbiome. By interacting with the aryl hydrocarbon receptor, various tryptophan metabolites modulate several metalloproteinases regulating brain Aβ peptide levels under normal and pathological conditions such as AD. In particular, interesting data reviewed here show that 5-HIAA and KYNA stimulate NEP activity/expression to prevent Aβ peptide-induced neurotoxicity. These data open promising perspectives for the development of tryptophan metabolite-based therapies against AD.
-
7.
Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer's Disease.
Gião, T, Saavedra, J, Cotrina, E, Quintana, J, Llop, J, Arsequell, G, Cardoso, I
International journal of molecular sciences. 2020;(6)
Abstract
Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer's disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.
-
8.
The Interplay between Diabetes and Alzheimer's Disease-In the Hunt for Biomarkers.
Kubis-Kubiak, A, Dyba, A, Piwowar, A
International journal of molecular sciences. 2020;(8)
Abstract
The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.
-
9.
Research Progress of Alzheimer's Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis.
Li, X, Xuan, W, Chen, D, Gao, H, Wang, G, Guo, Q, Wang, Y, Song, H, Cai, B
Journal of Alzheimer's disease : JAD. 2020;(4):1315-1338
Abstract
It is widely recognized that Alzheimer's disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD.
-
10.
Resveratrol targeting tau proteins, amyloid-beta aggregations, and their adverse effects: An updated review.
Ashrafizadeh, M, Zarrabi, A, Najafi, M, Samarghandian, S, Mohammadinejad, R, Ahn, KS
Phytotherapy research : PTR. 2020;(11):2867-2888
Abstract
Resveratrol (Res) is a non-flavonoid compound with pharmacological actions such as antioxidant, antiinflammatory, hepatoprotective, antidiabetes, and antitumor. This plant-derived chemical has a long history usage in treatment of diseases. The excellent therapeutic impacts of Res and its capability in penetration into blood-brain barrier have made it an appropriate candidate in the treatment of neurological disorders (NDs). Tau protein aggregations and amyloid-beta (Aβ) deposits are responsible for the induction of NDs. A variety of studies have elucidated the role of these aggregations in NDs and the underlying molecular pathways in their development. In the present review, based on the recently published articles, we describe that how Res administration could inhibit amyloidogenic pathway and stimulate processes such as autophagy to degrade Aβ aggregations. Besides, we demonstrate that Res supplementation is beneficial in dephosphorylation of tau proteins and suppressing their aggregations. Then, we discuss molecular pathways and relate them to the treatment of NDs.