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Pathogenesis of 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 Neurobiology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 70500

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Dr. Agueda A. Rostagno

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NYU, Department of Pathology, Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Interests: Alzheimer's disease; amyloidosis; neurodegenerative disorders, autophagy; apoptosis; mitochondrial dysfunction; oxidative stress; metabolic dysregulation; cerebral amyloid angiopathy; molecular chaperones; immunohistochemistry; neuroinflammation
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Prof. Dr. Agnieszka Baranowska-Bik

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Department of Endocrinology, Centre of Postgraduate Medical Education, Cegłowska 80, 01-809 Warsaw, Poland
Interests: skeletal muscle; muscle cachexia; cyto- and myokines; kinases; autophagy; apoptosis; lipid rafts; cholesterol; isoprenoids; Alzheimer's disease

Prof. Dr. Arkadiusz Orzechowski

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Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences—SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland
Interests: skeletal muscle; muscle cachexia; cyto- and myokines; kinases; autophagy; apoptosis; lipid rafts; cholesterol; isoprenoids; Alzheimer's disease
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Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

This special issue is focused on the effort to sum up contemporary knowledge referred to pathogenesis of Alzheimer’s Disease (AD). More than a century ago, German psychiatrist, professor of neuropathology, Alois Alzheimer described the most serious form of an age-related progressive neurodegenerative disorder in human beings. In the familial form, mutations in three major genes (amyloid precursor protein (APP) gene, presenilin1 (PSEN1) gene and presenilin 2 (PSEN2) gene are indicated. In turn, it is widely accepted that sporadic form of AD (more than 95% cases) is multifactorial and the prevalence is significantly higher at > 65 years and older. Overall, genetic complexity, epigenetic control and metabolic turmoils make the view of disease ambiguous and hard to find the causal relationships between different possible molecular etiologic factors. Extracellular senile plagues (beta-amyloid deposits), and intracellular neurofibrillary tangles (hyperphosphorylated tau-protein) are the most prominent characteristic markers of AD. Because of growing elderly the WHO prognosis for 2050 is more than 115 million individuals will be affected. The severity of AD is that affected people are sedentary and totally dependent on nursing care. Today, AD is the most expensive disease. 21^st of September is the International Alzheimer’s Disease Day making this opportunity to encourage various specialists for submissions.

Prof. Dr. Agueda A. Rostagno
Prof. Dr. Agnieszka Baranowska-Bik
Prof. Dr. Arkadiusz Orzechowski
Guest Editors

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Intersection between Cognitive Impairment and Metabolic Alterations in the Molecular Mechanisms of Neurodegeneration in International Journal of Molecular Sciences (3 articles)

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Editorial

Jump to: Research, Review

4 pages, 176 KiB

Open AccessEditorial

Pathogenesis of Alzheimer’s Disease

by Agueda A. Rostagno

Int. J. Mol. Sci. 2023, 24(1), 107; https://doi.org/10.3390/ijms24010107 - 21 Dec 2022

Cited by 26 | Viewed by 7859

Abstract

Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases [...] Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

Research

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15 pages, 1655 KiB

Open AccessArticle

Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice

by Jennifer M. Mattar, Mark Majchrzak, Jaclyn Iannucci, Sydney Bartman, John K. Robinson and Paula Grammas

Int. J. Mol. Sci. 2022, 23(7), 3921; https://doi.org/10.3390/ijms23073921 - 01 Apr 2022

Cited by 9 | Viewed by 3067

Abstract

Late-onset Alzheimer’s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown to strongly increase the risk of cardiovascular disease and diabetes, conditions which have been strongly linked to an increased risk for developing AD. Little is known about how the WD may contribute to, or enhance, the increased risk presented by possession of the ApoE4 allele. To model this interaction over the course of a lifetime, we exposed male and female homozygote ApoE4 knock-in mice and wild-type controls to nine months of a high-fat WD or standard chow diet. At eleven months of age, the mice were tested for glucose tolerance and then for general activity and spatial learning and memory. Postmortem analysis of liver function and neuroinflammation in the brain was also assessed. Our results suggest that behavior impairments resulted from the convergence of interacting metabolic alterations, made worse in a male ApoE4 mice group who also showed liver dysfunction, leading to a higher level of inflammatory cytokines in the brain. Interestingly, female ApoE4 mice on a WD revealed impairments in spatial learning and memory without the observed liver dysfunction or increase in inflammatory markers in the brain. These results suggest multiple direct and indirect pathways through which ApoE and diet-related factors interact. The striking sex difference in markers of chronic neuroinflammation in male ApoE4 mice fed the high-fat WD suggests a specific mechanism of interaction conferring significant enhanced LOAD risk for humans with the ApoE4 allele, which may differ between sexes. Additionally, our results suggest researchers exercise caution when designing and interpreting results of experiments employing a WD, being careful not to assume a WD impacts both sexes by the same mechanisms. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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19 pages, 3001 KiB

Open AccessArticle

Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors

by Michaela K. Back, Sonia Ruggieri, Eric Jacobi and Jakob von Engelhardt

Int. J. Mol. Sci. 2021, 22(12), 6298; https://doi.org/10.3390/ijms22126298 - 11 Jun 2021

Cited by 6 | Viewed by 2867

Abstract

Onset and progression of Alzheimer’s disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aβ) toxicity. NMDAR expression, on the other hand, can be affected by Aβ. We tested whether the high vulnerability of neocortical neurons for Aβ-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aβ. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aβ-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aβ-overexpression. NMDARs were required for both Aβ-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aβ-mediated regulation of NMDAR expression and the role of NMDARs in Aβ pathophysiology in the somatosensory cortex. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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17 pages, 2885 KiB

Open AccessArticle

Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

by Silvia Zampar and Oliver Wirths

Int. J. Mol. Sci. 2021, 22(10), 5191; https://doi.org/10.3390/ijms22105191 - 14 May 2021

Cited by 7 | Viewed by 2888

Abstract

The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ_4–42 is among the most abundant. To understand whether soluble Aβ_4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ_4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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14 pages, 2257 KiB

Open AccessArticle

Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer’s Disease

by Qiyue Ding, Nataliia V. Shults, Sergiy G. Gychka, Brent T. Harris and Yuichiro J. Suzuki

Int. J. Mol. Sci. 2021, 22(4), 1687; https://doi.org/10.3390/ijms22041687 - 08 Feb 2021

Cited by 63 | Viewed by 3892

Abstract

Alzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer’s disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer’s disease. In summary, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer’s disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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Review

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22 pages, 11800 KiB

Open AccessReview

Mechanistic Insights into Selective Autophagy Subtypes in Alzheimer’s Disease

by Xinjie Guan, Ashok Iyaswamy, Sravan Gopalkrishnashetty Sreenivasmurthy, Chengfu Su, Zhou Zhu, Jia Liu, Yuxuan Kan, King-Ho Cheung, Jiahong Lu, Jieqiong Tan and Min Li

Int. J. Mol. Sci. 2022, 23(7), 3609; https://doi.org/10.3390/ijms23073609 - 25 Mar 2022

Cited by 13 | Viewed by 3694

Abstract

Eukaryotic cells possess a plethora of regulatory mechanisms to maintain homeostasis and ensure proper biochemical functionality. Autophagy, a central, conserved self-consuming process of the cell, ensures the timely degradation of damaged cellular components. Several studies have demonstrated the important roles of autophagy activation in mitigating neurodegenerative diseases, especially Alzheimer’s disease (AD). However, surprisingly, activation of macroautophagy has not shown clinical efficacy. Hence, alternative strategies are urgently needed for AD therapy. In recent years, selective autophagy has been reported to be involved in AD pathology, and different subtypes have been identified, such as aggrephagy, mitophagy, reticulophagy, lipophagy, pexophagy, nucleophagy, lysophagy and ribophagy. By clarifying the underlying mechanisms governing these various subtypes, we may come to understand how to control autophagy to treat AD. In this review, we summarize the latest findings concerning the role of selective autophagy in the pathogenesis of AD. The evidence overwhelmingly suggests that selective autophagy is an active mechanism in AD pathology, and that regulating selective autophagy would be an effective strategy for controlling this pathogenesis. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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23 pages, 1262 KiB

Open AccessReview

Insulin and Insulin Resistance in Alzheimer’s Disease

by Aleksandra Sędzikowska and Leszek Szablewski

Int. J. Mol. Sci. 2021, 22(18), 9987; https://doi.org/10.3390/ijms22189987 - 15 Sep 2021

Cited by 98 | Viewed by 9025

Abstract

Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood–brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer’s disease. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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25 pages, 2019 KiB

Open AccessReview

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

by Anna Litwiniuk, Wojciech Bik, Małgorzata Kalisz and Agnieszka Baranowska-Bik

Int. J. Mol. Sci. 2021, 22(11), 5603; https://doi.org/10.3390/ijms22115603 - 25 May 2021

Cited by 24 | Viewed by 5338

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid β (Aβ) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1β signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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21 pages, 2616 KiB

Open AccessReview

Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

by Chanchal Sharma, Sehwan Kim, Youngpyo Nam, Un Ju Jung and Sang Ryong Kim

Int. J. Mol. Sci. 2021, 22(9), 4850; https://doi.org/10.3390/ijms22094850 - 03 May 2021

Cited by 86 | Viewed by 7457

Abstract

Alzheimer’s disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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34 pages, 3548 KiB

Open AccessReview

Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

by Wieke M. van Oostveen and Elizabeth C. M. de Lange

Int. J. Mol. Sci. 2021, 22(4), 2110; https://doi.org/10.3390/ijms22042110 - 20 Feb 2021

Cited by 74 | Viewed by 17399

Abstract

Background. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death. Introduction. In AD, pathological changes occur many years before disease onset. Since disease-modifying therapies may be the most beneficial in the early stages of AD, biomarkers for the early diagnosis and longitudinal monitoring of disease progression are essential. Multiple imaging techniques with associated biomarkers are used to identify and monitor AD. Aim. In this review, we discuss the contemporary early diagnosis and longitudinal monitoring of AD with imaging techniques regarding their diagnostic utility, benefits and limitations. Additionally, novel techniques, applications and biomarkers for AD research are assessed. Findings. Reduced hippocampal volume is a biomarker for neurodegeneration, but atrophy is not an AD-specific measure. Hypometabolism in temporoparietal regions is seen as a biomarker for AD. However, glucose uptake reflects astrocyte function rather than neuronal function. Amyloid-β (Aβ) is the earliest hallmark of AD and can be measured with positron emission tomography (PET), but Aβ accumulation stagnates as disease progresses. Therefore, Aβ may not be a suitable biomarker for monitoring disease progression. The measurement of tau accumulation with PET radiotracers exhibited promising results in both early diagnosis and longitudinal monitoring, but large-scale validation of these radiotracers is required. The implementation of new processing techniques, applications of other imaging techniques and novel biomarkers can contribute to understanding AD and finding a cure. Conclusions. Several biomarkers are proposed for the early diagnosis and longitudinal monitoring of AD with imaging techniques, but all these biomarkers have their limitations regarding specificity, reliability and sensitivity. Future perspectives. Future research should focus on expanding the employment of imaging techniques and identifying novel biomarkers that reflect AD pathology in the earliest stages. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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35 pages, 6395 KiB

Open AccessReview

Metals in Imaging of Alzheimer’s Disease

by Olga Krasnovskaya, Daniil Spector, Alexander Zlobin, Kirill Pavlov, Peter Gorelkin, Alexander Erofeev, Elena Beloglazkina and Alexander Majouga

Int. J. Mol. Sci. 2020, 21(23), 9190; https://doi.org/10.3390/ijms21239190 - 02 Dec 2020

Cited by 10 | Viewed by 4084

Abstract

One of the hallmarks of Alzheimer’s disease (AD) is the deposition of amyloid plaques in the brain parenchyma, which occurs 7–15 years before the onset of cognitive symptoms of the pathology. Timely diagnostics of amyloid formations allows identifying AD at an early stage and initiating inhibitor therapy, delaying the progression of the disease. However, clinically used radiopharmaceuticals based on ¹¹C and ¹⁸F are synchrotron-dependent and short-lived. The design of new metal-containing radiopharmaceuticals for AD visualization is of interest. The development of coordination compounds capable of effectively crossing the blood-brain barrier (BBB) requires careful selection of a ligand moiety, a metal chelating scaffold, and a metal cation, defining the method of supposed Aβ visualization. In this review, we have summarized metal-containing drugs for positron emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) imaging of Alzheimer’s disease. The obtained data allow assessing the structure-ability to cross the BBB ratio. Full article

(This article belongs to the Special Issue Pathogenesis of Alzheimer's Disease)

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