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Advance on the Research of Alzheimer's Disease
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Advance on the Research of Alzheimer's Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 18227

Special Issue Editor

Prof. Dr. Gerhard Rammes

E-Mail Website
Guest Editor
Department of Anaesthesiology and Intensive Care Medicine, Technical University Munich, Ismaninger str. 22, 81675 Munich, Germany
Interests: electrophysiology; long-term potentiation; voltage-sensitive-dye imaging; Alzheimer; anesthetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The incidence of dementia is increasing at an alarming rate and is a major modern public health concern. Alzheimer’s disease (AD), a neurodegenerative disorder with a rising incidence among elderly people, is the most common form of dementia and is characterized by progressive cognitive impairment. The precise aetiology of AD is not fully clarified but is known to be complex and multifactorial, with a notable overlap between familial and non-familial forms but also with different forms of dementia, e.g., vascular dementia.

AD is characterized by chronic, progressive neurodegeneration, which involves early synaptotoxicity and only at later stages overt neuronal loss and associated brain atrophy.

Beyond the conventional Ab- and tau-targeted approaches, current knowledge about the pathophysiology of AD continues to grow and new findings related to synaptic dysfunction and neuroinflammation are the current focus. Particularly, aberrant-activated microglia and neurotoxic astrocytes have been identified, and the involvement of the complement system in synaptic pruning mechanisms and mitochondrial dysfunction appear to be important mediators, which all may contribute to synaptic loss and cognitive deficits, the hallmarks of AD.

Additionally, the identification of molecular links between Alzheimer's disease, diabetes mellitus and other neurodegenerative diseases, likely to synergistically act in promoting AD pathology, may help to understand the early and late molecular mechanisms of AD.

Detailing the mechanisms on the molecular level and their neurotoxic effects is essential for developing urgently required new treatment strategies to fight this devastating disease.

In this Special Issue of IJMS, we are striving to gather innovative and important findings that provide a comprehensive view on the molecular mechanisms mediating the pathogenesis of AD.

Prof. Dr. Gerhard Rammes
Guest Editor

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Published Papers (7 papers)

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Editorial

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3 pages, 184 KiB  
Editorial
Molecular Mechanism of Alzheimer’s Disease
by Gerhard Rammes
Int. J. Mol. Sci. 2023, 24(23), 16837; https://doi.org/10.3390/ijms242316837 - 28 Nov 2023
Cited by 2 | Viewed by 1240
Abstract
Neurodegenerative disorders are a major public health concern [...] Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)

Research

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9 pages, 970 KiB  
Communication
New Highly Selective BACE1 Inhibitors and Their Effects on Dendritic Spine Density In Vivo
by Katrin Pratsch, Chie Unemura, Mana Ito, Stefan F. Lichtenthaler, Naotaka Horiguchi and Jochen Herms
Int. J. Mol. Sci. 2023, 24(15), 12283; https://doi.org/10.3390/ijms241512283 - 31 Jul 2023
Cited by 6 | Viewed by 2010
Abstract
β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered a therapeutic target to combat Alzheimer’s disease by reducing β-amyloid in the brain. To date, all clinical trials involving the inhibition of BACE1 have been discontinued due to a lack of efficacy or undesirable [...] Read more.
β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered a therapeutic target to combat Alzheimer’s disease by reducing β-amyloid in the brain. To date, all clinical trials involving the inhibition of BACE1 have been discontinued due to a lack of efficacy or undesirable side effects such as cognitive worsening. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural synaptic plasticity, most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6) which is exclusively processed by BACE1 and is required for dendritic spine plasticity. Given that BACE1 has significant amino acid similarity with its homolog BACE2, the inhibition of BACE2 may cause some of the side effects, as most BACE inhibitors do not discriminate between the two. In this study, we used newly developed BACE inhibitors that have a different chemotype from previously developed inhibitors and a high selectivity for BACE1 over BACE2. By using longitudinal in vivo two-photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with highly selective BACE1 inhibitors. Treatment with those inhibitors showed a reduction in soluble Sez6 (sSez6) levels to 27% (elenbecestat, Biogen, Eisai Co., Ltd., Tokyo, Japan), 17% (Shionogi compound 1) and 39% (Shionogi compound 2), compared to animals fed with vehicle pellets. We observed a significant decrease in the number of dendritic spines with Shionogi compound 1 after 21 days of treatment but not with Shionogi compound 2 or with elenbecestat, which did not show cognitive worsening in clinical trials. In conclusion, highly selective BACE1 inhibitors do alter dendritic spine density similar to non-selective inhibitors if soluble (sSez6) levels drop too much. Low-dose BACE1 inhibition might be reasonable if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first week of treatment. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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20 pages, 3718 KiB  
Article
The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aβ1–42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices
by Dai Shi, Jaime K. Y. Wong, Kaichuan Zhu, Peter G. Noakes and Gerhard Rammes
Int. J. Mol. Sci. 2023, 24(2), 912; https://doi.org/10.3390/ijms24020912 - 4 Jan 2023
Cited by 6 | Viewed by 2160
Abstract
It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer’s disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of [...] Read more.
It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer’s disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how β-amyloid peptide 1–42 (Aβ1–42), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aβ1–42, Iso or Xe and the combination of Aβ1–42 with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aβ1–42 elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aβ1–42 both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aβ1–42-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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16 pages, 3585 KiB  
Article
PS1 Affects the Pathology of Alzheimer’s Disease by Regulating BACE1 Distribution in the ER and BACE1 Maturation in the Golgi Apparatus
by Nuomin Li, Yunjie Qiu, Hao Wang, Juan Zhao and Hong Qing
Int. J. Mol. Sci. 2022, 23(24), 16151; https://doi.org/10.3390/ijms232416151 - 18 Dec 2022
Cited by 4 | Viewed by 2288
Abstract
Neuritic plaques are one of the major pathological hallmarks of Alzheimer’s disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretase. BACE1 is the main [...] Read more.
Neuritic plaques are one of the major pathological hallmarks of Alzheimer’s disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretase. BACE1 is the main β-secretase in the pathogenic process of Alzheimer’s disease, which is believed to be a rate-limiting step of Aβ production. Presenilin 1 (PS1) is the active center of the γ-secretase that participates in the APP hydrolysis process. Mutations in the PS1 gene (PSEN1) are the most common cause of early onset familial Alzheimer’s disease (FAD). The PSEN1 mutations can alter the activity of γ-secretase on the cleavage of APP. Previous studies have shown that PSEN1 mutations increase the expression and activity of BACE1 and that BACE1 expression and activity are elevated in the brains of PSEN1 mutant knock-in mice, compared with wild-type mice, as well as in the cerebral cortex of FAD patients carrying PSEN1 mutations, compared with sporadic AD patients and controls. Here, we used a Psen1 knockout cell line and a PS1 inhibitor to show that PS1 affects the expression of BACE1 in vitro. Furthermore, we used sucrose gradient fractionation combined with western blotting to analyze the distribution of BACE1, combined with a time-lapse technique to show that PS1 upregulates the distribution and trafficking of BACE1 in the endoplasmic reticulum, Golgi, and endosomes. More importantly, we found that the PSEN1 mutant S170F increases the distribution of BACE1 in the endoplasmic reticulum and changes the ratio of mature BACE1 in the trans-Golgi network. The effect of PSEN1 mutations on BACE1 may contribute to determining the phenotype of early onset FAD. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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23 pages, 2640 KiB  
Article
AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer’s and Parkinson’s Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery
by Coralie Di Scala, Nicholas Armstrong, Henri Chahinian, Eric Chabrière, Jacques Fantini and Nouara Yahi
Int. J. Mol. Sci. 2022, 23(21), 13383; https://doi.org/10.3390/ijms232113383 - 2 Nov 2022
Cited by 8 | Viewed by 3314
Abstract
Neurodegenerative disorders are a major public health issue. Despite decades of research efforts, we are still seeking an efficient cure for these pathologies. The initial paradigm of large aggregates of amyloid proteins (amyloid plaques, Lewis bodies) as the root cause of Alzheimer’s and [...] Read more.
Neurodegenerative disorders are a major public health issue. Despite decades of research efforts, we are still seeking an efficient cure for these pathologies. The initial paradigm of large aggregates of amyloid proteins (amyloid plaques, Lewis bodies) as the root cause of Alzheimer’s and Parkinson’s diseases has been mostly dismissed. Instead, membrane-bound oligomers forming Ca2+-permeable amyloid pores are now considered appropriate targets for these diseases. Over the last 20 years, our group deciphered the molecular mechanisms of amyloid pore formation, which appeared to involve a common pathway for all amyloid proteins, including Aβ (Alzheimer) and α-synuclein (Parkinson). We then designed a short peptide (AmyP53), which prevents amyloid pore formation by targeting gangliosides, the plasma membrane receptors of amyloid proteins. Herein, we show that aqueous solutions of AmyP53 are remarkably stable upon storage at temperatures up to 45 °C for several months. AmyP53 appeared to be more stable in whole blood than in plasma. Pharmacokinetics studies in rats demonstrated that the peptide can rapidly and safely reach the brain after intranasal administration. The data suggest both the direct transport of AmyP53 via the olfactory bulb (and/or the trigeminal nerve) and an indirect transport via the circulation and the blood–brain barrier. In vitro experiments confirmed that AmyP53 is as active as cargo peptides in crossing the blood–brain barrier, consistent with its amino acid sequence specificities and physicochemical properties. Overall, these data open a route for the use of a nasal spray formulation of AmyP53 for the prevention and/or treatment of Alzheimer’s and Parkinson’s diseases in future clinical trials in humans. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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19 pages, 3663 KiB  
Article
Effect of Obesity and High-Density Lipoprotein Concentration on the Pathological Characteristics of Alzheimer’s Disease in High-Fat Diet-Fed Mice
by Moonseok Choi, Dongsoo Kim, Young-Jin Youn, Junghwa Ryu and Yun Ha Jeong
Int. J. Mol. Sci. 2022, 23(20), 12296; https://doi.org/10.3390/ijms232012296 - 14 Oct 2022
Cited by 6 | Viewed by 2674
Abstract
The typical pathological features of Alzheimer’s disease (AD) are the accumulation of amyloid plaques in the brain and reactivity of glial cells such as astrocytes and microglia. Clinically, the development of AD and obesity are known to be correlated. In this study, we [...] Read more.
The typical pathological features of Alzheimer’s disease (AD) are the accumulation of amyloid plaques in the brain and reactivity of glial cells such as astrocytes and microglia. Clinically, the development of AD and obesity are known to be correlated. In this study, we analyzed the changes in AD pathological characteristics in 5XFAD mice after obesity induction through a high-fat diet (HFD). Surprisingly, high-density lipoprotein and apolipoprotein AI (APOA-I) serum levels were increased without low-density lipoprotein alteration in both HFD groups. The reactivity of astrocytes and microglia in the dentate gyrus of the hippocampus and fornix of the hypothalamus in 5XFAD mice was decreased in the transgenic (TG)-HFD high group. Finally, the accumulation of amyloid plaques in the dentate gyrus region of the hippocampus was also significantly decreased in the TG-HFD high group. These results suggest that increased high-density lipoprotein level, especially with increased APOA-I serum level, alleviates the pathological features of AD and could be a new potential therapeutic strategy for AD treatment. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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Review

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14 pages, 1164 KiB  
Review
The Asparaginyl Endopeptidase Legumain: An Emerging Therapeutic Target and Potential Biomarker for Alzheimer’s Disease
by Mingke Song
Int. J. Mol. Sci. 2022, 23(18), 10223; https://doi.org/10.3390/ijms231810223 - 6 Sep 2022
Cited by 12 | Viewed by 3495
Abstract
Alzheimer’s disease (AD) is incurable dementia closely associated with aging. Most cases of AD are sporadic, and very few are inherited; the pathogenesis of sporadic AD is complex and remains to be elucidated. The asparaginyl endopeptidase (AEP) or legumain is the only recognized [...] Read more.
Alzheimer’s disease (AD) is incurable dementia closely associated with aging. Most cases of AD are sporadic, and very few are inherited; the pathogenesis of sporadic AD is complex and remains to be elucidated. The asparaginyl endopeptidase (AEP) or legumain is the only recognized cysteine protease that specifically hydrolyzes peptide bonds after asparagine residues in mammals. The expression level of AEPs in healthy brains is far lower than that of peripheral organs. Recently, growing evidence has indicated that aging may upregulate and overactivate brain AEPs. The overactivation of AEPs drives the onset of AD through cleaving tau and amyloid precursor proteins (APP), and SET, an inhibitor of protein phosphatase 2A (PP2A). The AEP-mediated cleavage of these peptides enhances amyloidosis, promotes tau hyperphosphorylation, and ultimately induces neurodegeneration and cognitive impairment. Upregulated AEPs and related deleterious reactions constitute upstream events of amyloid/tau toxicity in the brain, and represent early pathological changes in AD. Thus, upregulated AEPs are an emerging drug target for disease modification and a potential biomarker for predicting preclinical AD. However, the presence of the blood–brain barrier greatly hinders establishing body-fluid-based methods to measure brain AEPs. Research on AEP-activity-based imaging probes and our recent work suggest that the live brain imaging of AEPs could be used to evaluate its predictive efficacy as an AD biomarker. To advance translational research in this area, AEP imaging probes applicable to human brain and AEP inhibitors with good druggability are urgently needed. Full article
(This article belongs to the Special Issue Advance on the Research of Alzheimer's Disease)
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