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Molecular Advances in Alzheimer's Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 19043

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Dr. María-Salud García-Ayllón

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Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550 Sant Joan d’Alacant, Spain
Interests: Alzheimer’s disease; Parkinson’s disease; biomarkers; protein’s deposition; neuroinflammation
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Dear Colleagues,

Alzheimer’s disease (AD), the most common cause of dementia among the elderly, is characterized by loss of memory and other cognitive functions. The main neuropathological changes associated with AD include synaptic and neuronal loss, astrogliosis, and protein deposition. Despite these neuropathological hallmarks, emerging data suggest that the disease has a complex aetiology; neuroinflammation, oxidative stress, and mitochondrial dysfunction seem to play an important role in the pathophysiology of mild cognitive impairment and AD, as well as in other neurodegenerative disorders such as Parkinson’s disease. However, the underlying molecular mechanisms associated with these alterations are still elusive. Unfortunately, AD diagnosis occurs at a stage in which the underlying pathology has reached an advanced and possibly irreversible state. Therefore, the major challenges in AD research are to identify biomarkers for early diagnosis and finding therapeutic strategies that prevent the development of the pathology. For that, we need to decipher the cellular and molecular mechanisms that underlie AD and other neurodegenerative diseases, as well as their progression and severity.

This Special Issue will focus on reviews and original data manuscripts that concern (1) the molecular mechanism of Alzheimer’s and other neurodegenerative diseases; (2) molecular targets for new Alzheimer’s biomarkers; (3) the genetics of Alzheimer’s and other neurogenerative diseases; (4) molecular targets for new therapeutic techniques for Alzheimer’s; (5) the molecular mechanism of neuroinflammation in neurodegenerative diseases.

Dr. María-Salud García-Ayllón
Guest Editor

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Keywords

molecular targets
neurodegenerative diseases
Alzheimer’s disease
Parkinson’s
neuroinflammation

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Published Papers (9 papers)

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Research

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15 pages, 1813 KiB

Open AccessArticle

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

by Yi-Chun Chen, Shih-Cheng Chang, Yun-Shien Lee, Wei-Min Ho, Yu-Hua Huang, Yah-Yuan Wu, Yi-Chuan Chu, Kuan-Hsuan Wu, Li-Shan Wei, Hung-Li Wang and Ching-Chi Chiu

Int. J. Mol. Sci. 2023, 24(4), 4085; https://doi.org/10.3390/ijms24044085 - 17 Feb 2023

Cited by 8 | Viewed by 2839

Abstract

Translocase of outer mitochondrial membrane 40 (TOMM40) is located in the outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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28 pages, 9846 KiB

Open AccessArticle

Stabilization of Monomeric Tau Protein by All D-Enantiomeric Peptide Ligands as Therapeutic Strategy for Alzheimer’s Disease and Other Tauopathies

by Tim Altendorf, Ian Gering, Beatrix Santiago-Schübel, Selma Aghabashlou Saisan, Gültekin Tamgüney, Markus Tusche, Dominik Honold, Sarah Schemmert, Wolfgang Hoyer, Jeannine Mohrlüder and Dieter Willbold

Int. J. Mol. Sci. 2023, 24(3), 2161; https://doi.org/10.3390/ijms24032161 - 21 Jan 2023

Cited by 4 | Viewed by 1638

Abstract

Alzheimer’s disease and other tauopathies are the world’s leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases. During the onset of tauopathies, tau undergoes structural changes and posttranslational modifications and aggregates into amyloid fibrils that are able to spread with a prion-like behavior. Up to now, there is no therapeutic agent which effectively controls or reverses the disease. Most of the therapeutics that were developed and underwent clinical trials targeted misfolded or aggregated forms of tau. In the current manuscript, we present the selection and characterization of two all D-enantiomeric peptides that bind monomeric tau protein with a low nanomolar K_D, stabilize tau in its monomeric intrinsically disordered conformation, and stop the conversion of monomers into aggregates. We show that the effect of the two all D-enantiomeric peptides is strong enough to stop ongoing tau aggregation in vitro and is able to significantly reduce tau fibril assembly in cell culture. Both compounds may serve as new lead components for the development of therapeutic agents against Alzheimer’s disease and other tauopathies. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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18 pages, 3439 KiB

Open AccessArticle

Presenilin 1 Modulates Acetylcholinesterase Trafficking and Maturation

by María-Ángeles Cortés-Gómez, Víctor M. Barberá, Jordi Alom, Javier Sáez-Valero and María-Salud García-Ayllón

Int. J. Mol. Sci. 2023, 24(2), 1437; https://doi.org/10.3390/ijms24021437 - 11 Jan 2023

Cited by 1 | Viewed by 1254

Abstract

In Alzheimer’s disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the presence of a considerable enzymatically inactive pool in the brain. In the present study, we validated previous findings, and, since inactive forms could result from post-translational modifications, we analyzed the glycosylation of AChE by lectin binding in brain samples from sporadic and familial AD (sAD and fAD). Most of the enzymatically active AChE was bound to lectins Canavalia ensiformis (Con A) and Lens culinaris agglutinin (LCA) that recognize terminal mannoses, whereas Western blot assays showed a very low percentage of AChE protein being recognized by the lectin. This indicates that active and inactive forms of AChE vary in their glycosylation pattern, particularly in the presence of terminal mannoses in active ones. Moreover, sAD subjects showed reduced binding to terminal mannoses compared to non-demented controls, while, for fAD patients that carry mutations in the PSEN1 gene, the binding was higher. The role of presenilin-1 (PS1) in modulating AChE glycosylation was then studied in a cellular model that overexpresses PS1 (CHO-PS1). In CHO-PS1 cells, binding to LCA indicates that AChE displays more terminal mannoses in oligosaccharides with a fucosylated core. Immunocytochemical assays also demonstrated increased presence of AChE in the trans-Golgi. Moreover, AChE enzymatic activity was higher in plasmatic membrane of CHO-PS1 cells. Thus, our results indicate that PS1 modulates trafficking and maturation of AChE in Golgi regions favoring the presence of active forms in the membrane. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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23 pages, 5079 KiB

Open AccessArticle

Fecal Volatile Organic Compounds and Microbiota Associated with the Progression of Cognitive Impairment in Alzheimer’s Disease

by Cristina Ubeda, María D. Vázquez-Carretero, Andrea Luque-Tirado, Rocío Ríos-Reina, Ricardo Rubio-Sánchez, Emilio Franco-Macías, Pablo García-Miranda, María L. Calonge and María J. Peral

Int. J. Mol. Sci. 2023, 24(1), 707; https://doi.org/10.3390/ijms24010707 - 31 Dec 2022

Cited by 6 | Viewed by 2193

Abstract

Metabolites produced by an altered gut microbiota might mediate the effects in the brain. Among metabolites, the fecal volatile organic compounds (VOCs) are considered to be potential biomarkers. In this study, we examined both the VOCs and bacterial taxa in the feces from healthy subjects and Alzheimer’s disease (AD) patients at early and middle stages. Remarkably, 29 fecal VOCs and 13 bacterial genera were differentiated from the healthy subjects and the AD patients. In general, higher amounts of acids and esters were found in in the feces of the AD patients and terpenes, sulfur compounds and aldehydes in the healthy subjects. At the early stage of AD, the most relevant VOCs with a higher abundance were short-chain fatty acids and their producing bacteria, Faecalibacterium and Lachnoclostridium. Coinciding with the development of dementia in the AD patients, parallel rises of heptanoic acid and Peptococcus were observed. At a more advanced stage of AD, the microbiota and volatiles shifted towards a profile in the feces with increases in hexanoic acid, Ruminococcus and Blautia. The most remarkable VOCs that were associated with the healthy subjects were 4-ethyl-phenol and dodecanol, together with their possible producers Clostridium and Coprococcus. Our results revealed a VOCs and microbiota crosstalk in AD development and their profiles in the feces were specific depending on the stage of AD. Additionally, some of the most significant fecal VOCs identified in our study could be used as potential biomarkers for the initiation and progression of AD. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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14 pages, 2126 KiB

Open AccessArticle

The Role of Aldose Reductase in Beta-Amyloid-Induced Microglia Activation

by Yu-Kai Huang, Chia-Chun Liu, Shining Wang, Hui-Chun Cheng, Chandler Meadows and Kun-Che Chang

Int. J. Mol. Sci. 2022, 23(23), 15088; https://doi.org/10.3390/ijms232315088 - 01 Dec 2022

Cited by 10 | Viewed by 2084

Abstract

The occurrence of Alzheimer’s disease has been associated with the accumulation of beta-amyloid (β-amyloid) plaques. These plaques activate microglia to secrete inflammatory molecules, which damage neurons in the brain. Thus, understanding the underlying mechanism of microglia activation can provide a therapeutic strategy for alleviating microglia-induced neuroinflammation. The aldose reductase (AR) enzyme catalyzes the reduction of glucose to sorbitol in the polyol pathway. In addition to mediating diabetic complications in hyperglycemic environments, AR also helps regulate inflammation in microglia. However, little is known about the role of AR in β-amyloid-induced inflammation in microglia and subsequent neuronal death. In this study, we confirmed that AR inhibition attenuates increased β-amyloid-induced reactive oxygen species and tumor necrosis factor α secretion by suppressing ERK signaling in BV₂ cells. In addition, we are the first to report that AR inhibition reduced the phagocytotic capability and cell migration of BV₂ cells in response to β-amyloid. To further investigate the protective role of the AR inhibitor sorbinil in neurons, we co-cultured β-amyloid-induced microglia with stem cell-induced neurons. sorbinil ameliorated neuronal damage in both cells in the co-culture system. In summary, our findings reveal AR regulation of microglia activation as a novel therapeutic target for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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12 pages, 2916 KiB

Open AccessArticle

Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease

by Susan Adele Greenfield, Giovanni Ferrati, Clive W. Coen, Auguste Vadisiute, Zoltan Molnár, Sara Garcia-Rates, Sally Frautschy and Gregory M. Cole

Int. J. Mol. Sci. 2022, 23(21), 13119; https://doi.org/10.3390/ijms232113119 - 28 Oct 2022

Cited by 4 | Viewed by 1779

Abstract

The substantia nigra is generally considered to show significant cell loss not only in Parkinson’s but also in Alzheimer’s disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer’s pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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16 pages, 1556 KiB

Open AccessArticle

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

by Inmaculada Lopez-Font, Matthew P. Lennol, Guillermo Iborra-Lazaro, Henrik Zetterberg, Kaj Blennow and Javier Sáez-Valero

Int. J. Mol. Sci. 2022, 23(14), 7522; https://doi.org/10.3390/ijms23147522 - 07 Jul 2022

Cited by 3 | Viewed by 1937

Abstract

Reelin binds to the apolipoprotein E receptor apoER2 to activate an intracellular signaling cascade. The proteolytic cleavage of reelin follows receptor binding but can also occur independently of its binding to receptors. This study assesses whether reelin proteolytic fragments are differentially affected in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) subjects. CSF reelin species were analyzed by Western blotting, employing antibodies against the N- and C-terminal domains. In AD patients, we found a decrease in the 420 kDa full-length reelin compared with controls. In these patients, we also found an increase in the N-terminal 310 kDa fragment resulting from the cleavage at the so-called C-t site, whereas the 180 kDa fragment originated from the N-t site remained unchanged. Regarding the C-terminal proteolytic fragments, the 100 kDa fragment resulting from the cleavage at the C-t site also displayed increased levels, whilst the one resulting from the N-t site, the 250 kDa fragment, decreased. We also detected the presence of an aberrant reelin species with a molecular mass of around 500 kDa present in AD samples (34 of 43 cases), while it was absent in the 14 control cases analyzed. These 500 kDa species were only immunoreactive to N-terminal antibodies. We validated the occurrence of these aberrant reelin species in an Aβ42-treated reelin-overexpressing cell model. When we compared the AD samples from APOE genotype subgroups, we only found minor differences in the levels of reelin fragments associated to the APOE genotype, but interestingly, the levels of fragments of apoER2 were lower in APOE ε4 carriers with regards to APOE ε3/ε3. The altered proportion of reelin/apoER2 fragments and the occurrence of reelin aberrant species suggest a complex regulation of the reelin signaling pathway, which results impaired in AD subjects. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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18 pages, 3104 KiB

Open AccessArticle

Differences in Tau Seeding in Newborn and Adult Wild-Type Mice

by Isidro Ferrer, Pol Andrés-Benito, Paula Garcia-Esparcia, Irene López-Gonzalez, Diego Valiente, Mónica Jordán-Pirla, Margarita Carmona, Julia Sala-Jarque, Vanessa Gil and José Antonio del Rio

Int. J. Mol. Sci. 2022, 23(9), 4789; https://doi.org/10.3390/ijms23094789 - 26 Apr 2022

Cited by 3 | Viewed by 2409

Abstract

Alzheimer’s disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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Review

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20 pages, 976 KiB

Open AccessReview

Physiological and Pathological Remodeling of Cerebral Microvessels

by Pavel P. Tregub, Anton S. Averchuk, Tatyana I. Baranich, Maria V. Ryazanova and Alla B. Salmina

Int. J. Mol. Sci. 2022, 23(20), 12683; https://doi.org/10.3390/ijms232012683 - 21 Oct 2022

Cited by 5 | Viewed by 1888

Abstract

There is growing evidence that the remodeling of cerebral microvessels plays an important role in plastic changes in the brain associated with development, experience, learning, and memory consolidation. At the same time, abnormal neoangiogenesis, and deregulated regulation of microvascular regression, or pruning, could contribute to the pathogenesis of neurodevelopmental diseases, stroke, and neurodegeneration. Aberrant remodeling of microvesselsis associated with blood–brain barrier breakdown, development of neuroinflammation, inadequate microcirculation in active brain regions, and leads to the dysfunction of the neurovascular unit and progressive neurological deficits. In this review, we summarize current data on the mechanisms of blood vessel regression and pruning in brain plasticity and in Alzheimer’s-type neurodegeneration. We discuss some novel approaches to modulating cerebral remodeling and preventing degeneration-coupled aberrant microvascular activity in chronic neurodegeneration. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)

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