From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

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Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0350974 ◽

2007 ◽

Vol 35 (5) ◽

pp. 974-979 ◽

Cited By ~ 12

Author(s):

R.B. Parsons ◽

B.M. Austen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Protein Interactions ◽

Senile Plaques ◽

Amyloid Β ◽

Precursor Protein ◽

Amyloid Β Peptide ◽

Aβ Amyloid ◽

Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

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The impact of melatonin on antioxidant defense mechanisms in Alzheimer’s disease

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0012.8252 ◽

2018 ◽

Vol 72 ◽

pp. 1114-1122

Author(s):

Daria Malicka ◽

Dominika Markowska ◽

Jarosław Nuszkiewicz ◽

Karolina Szewczyk-Golec

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Defense Mechanisms ◽

Senile Plaques ◽

Biological Clock ◽

Cell Functions ◽

Increased Risk ◽

The Impact ◽

Phosphorylated Tau Protein

During aging, the increased risk of neurodegenerative disease development is observed. One of the most common and most serious disorders is Alzheimer’s disease manifested by the loss of nerve cell functions. In the course of the disease, extracellular senile plaques consisting of beta-amyloid and intracellular neurofibrillary tangles of hyper-phosphorylated tau protein are formed. As a result of aging, the repair potential of damaged nerve cells is reduced. Free radicals formed in excess generate augmented oxidative stress, which contributes to the damaging of biomolecules and the development of pathological changes. This mechanism is favored by a decrease in the efficiency of antioxidant enzymes and the deficiency of antioxidants, observed in aging organism. With age, the secretion of the pineal hormone melatonin, functioning as a biochemical biological clock, is significantly reduced. This compound has been proved to be a very effective antioxidant that plays a key role in protecting cells against excessive damage, especially in nervous tissue. Studies have shown that supplementation with exogenous melatonin can prevent oxidative stress-induced degeneration of neurons. Considering the action of melatonin and the pathogenesis of Alzheimer’s disease, the idea of using the hormone supplementation in the prevention and alleviation of the effects of the disease seems to be extremely interesting.

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Matrix metalloproteinases in peripheral blood and cerebrospinal fluid in patients with Alzheimer's disease

International Psychogeriatrics ◽

10.1017/s1041610210000827 ◽

2010 ◽

Vol 22 (6) ◽

pp. 966-972 ◽

Cited By ~ 45

Author(s):

Solveig Horstmann ◽

Leila Budig ◽

Humphrey Gardner ◽

James Koziol ◽

Michael Deuschle ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Matrix Metalloproteinases ◽

Senile Plaques ◽

Amyloid Β ◽

Post Mortem Brain ◽

Casein Zymography ◽

Pearson Correlations

ABSTRACTBackground: Deposition of amyloid β in senile plaques and in cerebral blood vessels is one hallmark of the pathogenesis of Alzheimer's disease (AD). The ability of several matrix metalloproteinases (MMPs) to degrade amyloid precursor protein leading to aggregation of amyloid β, as well as the increased expression of MMPs in post mortem brain tissue of Alzheimer's patients, indicate that MMPs play an important role in the pathogenesis of AD.Methods: We investigated levels of MMP-2,-3,-9 and -10 in plasma and cerebrospinal fluid (CSF) of AD patients (n = 14) by gelatin and casein zymography. Comparisons between AD patients and controls relative to levels of MMP-2, MMP-3, MMP-9, and MMP-10 were made with Wilcoxon rank statistics. Pearson correlations were computed as measures of association.Results: MMP-3 in AD was significantly elevated in plasma (p = 0.006) and there was a trend towards increase in CSF (p = 0.05). MMP-2 in CSF of AD patients was significantly decreased (p = 0.02) while levels in plasma remained unchanged. MMP-9 and MMP-10 could not be detected in CSF; MMP-10 was unchanged in plasma, but MMP-9 was significantly decreased (p = 0.02).Conclusions: These findings constitute further evidence for the important role of MMPs in the pathogenesis of AD.

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USP14 haploinsufficiency ameliorates Alzheimer’s disease-like pathology in APP/PS1 mice

10.21203/rs.3.rs-84968/v1 ◽

2020 ◽

Author(s):

Hua Xu ◽

Xueheng Wu ◽

Lu Liang ◽

Haoyu Chen ◽

Jia Xu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Senile Plaques ◽

Ubiquitin Proteasome System ◽

Spatial Learning And Memory ◽

Protein Levels ◽

Reported Study ◽

Ubiquitin Proteasome ◽

The Impact

Abstract Background: Alzheimer's disease (AD) is the most common cause of dementia; its main pathological features are neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (Tau) in the cell and extracellular beta-amyloid protein (Aβ)-based senile plaques (SP). The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells. Proteasome malfunction exists in AD patients and may promote the progression of the disease. USP14 is a deubiquitinating enzyme associated with the 19S proteasome. Functional inhibition of USP14 was shown to enhance proteasome proteolytic function, but no reported study has investigated the impact of genetic inhibition of USP14 on AD.Methods: Mice with heterozygous knockout of the Usp14 gene (USP14+/-) were generated and cross-bred with the APP/PS1 transgenic mice, the resultant offspring littermates were subjected to basal survival and growth analyses, and comparison of AD-like pathologies as detected with biochemical and histopathological methods and of cognitive function as assessed with the Morris water maze tests. Results:USP14 mRNA and protein levels in USP14+/- mice were decreased by ~50% compared with USP14+/+mice. The increases of total, K48 or K63 linked ubiquitinated proteins in APP/PS1 mouse brains were abolished in APP/PS1::USP14+/- mice. The increases in Aβ deposition and AD-associated phosphorylated Tau, senile plagues and neurofibrillary tangles, as well as spatial learning and memory decline induced by APP/PS1 were significantly attenuated in APP/PS1 mice. Conclusions: This study demonstrates that global knocking down USP14 protein expression by 50% is tolerable by mice and exhibits marked protection against AD-like pathologies in a widely used AD mouse model, favoring the exploration of moderate inhibition ofUSP14 as a potentially novel and viable therapy against AD.

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USP14 Haploinsufficiency Ameliorates Alzheimer’s Disease-Like Pathology in APP/PS1 Mice

10.21203/rs.3.rs-68805/v1 ◽

2020 ◽

Author(s):

Hua Xu ◽

Xueheng Wu ◽

Lu Liang ◽

Haoyu Chen ◽

Jia Xu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Senile Plaques ◽

Ubiquitin Proteasome System ◽

Spatial Learning And Memory ◽

Protein Levels ◽

Reported Study ◽

Ubiquitin Proteasome ◽

The Impact

Abstract Background: Alzheimer's disease (AD) is the most common cause of dementia; its main pathological features are neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (Tau) in the cell and extracellular beta-amyloid protein (Aβ)-based senile plaques (SP). The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells. Proteasome malfunction exists in AD patients and may promote the progression of the disease. USP14 is a deubiquitinating enzyme associated with the 19S proteasome. Functional inhibition of USP14 was shown to enhance proteasome proteolytic function, but no reported study has investigated the impact of genetic inhibition of USP14 on AD.Methods: Mice with heterozygous knockout of the Usp14 gene (USP14+/-) were generated and cross-bred with the APP/PS1 transgenic mice, the resultant offspring littermates were subjected to basal survival and growth analyses, and comparison of AD-like pathologies as detected with biochemical and histopathological methods and of cognitive function as assessed with the Morris water maze tests. Results:USP14 mRNA and protein levels in USP14+/- mice were decreased by ~50% compared with USP14+/+mice. The increases of total, K48 or K63 linked ubiquitinated proteins in APP/PS1 mouse brains were abolished in APP/PS1::USP14+/- mice. The increases in Aβ deposition and AD-associated phosphorylated Tau, senile plagues and neurofibrillary tangles, as well as spatial learning and memory decline induced by APP/PS1 were significantly attenuated in APP/PS1 mice. Conclusions: This study demonstrates that global knocking down USP14 protein expression by 50% is tolerable by mice and exhibits marked protection against AD-like pathologies in a widely used AD mouse model, favoring the exploration of moderate inhibition ofUSP14 as a potentially novel and viable therapy against AD.

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Dietary Fatty Acid Factors in Alzheimer’s Disease: A Review

Journal of Alzheimer s Disease ◽

10.3233/jad-200558 ◽

2020 ◽

Vol 78 (3) ◽

pp. 887-904

Author(s):

Tianying Zhang ◽

Xiaojuan Han ◽

Xiaohua Zhang ◽

Zhi Chen ◽

Yajing Mi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fatty Acids ◽

Fatty Acid ◽

Dietary Habits ◽

Epidemiological Studies ◽

Point Of View ◽

Dietary Fatty Acids ◽

Dietary Fatty Acid ◽

Beneficial Effects

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by brain function disorder and chronic cognitive function impairment. The onset of AD is complex and is mostly attributed to interactions between genetic factors and environmental factors. Lifestyle, dietary habits, and food consumption are likely to play indispensable functions in aged-related neurodegenerative diseases in elderly people. An increasing number of epidemiological studies have linked dietary fatty acid factors to AD, raising the point of view that fatty acid metabolism plays an important role in AD initiation and progression as well as in other central nervous system disorders. In this paper, we review the effects of the consumption of various dietary fatty acids on AD onset and progression and discuss the detrimental and beneficial effects of some typical fatty acids derived from dietary patterns on the pathology of AD. We outline these recent advances, and we recommend that healthy dietary lifestyles may contribute to preventing the occurrence and decreasing the pathology of AD.

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Microglia in Alzheimer’s Disease in the Context of Tau Pathology

Biomolecules ◽

10.3390/biom10101439 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1439 ◽

Cited By ~ 1

Author(s):

Juan Ramón Perea ◽

Marta Bolós ◽

Jesús Avila

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Molecular Mechanisms ◽

Senile Plaques ◽

Protein A ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Tau Pathology ◽

The Impact

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

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The impact of capsaicinoids on APP processing in Alzheimer’s disease in SH-SY5Y cells

Scientific Reports ◽

10.1038/s41598-020-66009-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Marcus O. W. Grimm ◽

Tamara Blümel ◽

Anna A. Lauer ◽

Daniel Janitschke ◽

Christoph Stahlmann ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Amyloid Β ◽

Insulin Degrading Enzyme ◽

App Processing ◽

Positive Effects ◽

Aβ Degradation ◽

The Impact

Abstract The vanilloid capsaicin is a widely consumed spice, known for its burning and “hot” sensation through activation of TRPV1 ion-channels, but also known to decrease oxidative stress, inflammation and influence tau-pathology. Beside these positive effects, little is known about its effects on amyloid-precursor-protein (APP) processing leading to amyloid-β (Aβ), the major component of senile plaques. Treatment of neuroblastoma cells with capsaicinoids (24 hours, 10 µM) resulted in enhanced Aβ-production and reduced Aβ-degradation, leading to increased Aβ-levels. In detailed analysis of the amyloidogenic-pathway, both BACE1 gene-expression as well as protein-levels were found to be elevated, leading to increased β-secretase-activity. Additionally, γ-secretase gene-expression as well as activity was enhanced, accompanied by a shift of presenilin from non-raft to raft membrane-domains where amyloidogenic processing takes place. Furthermore, impaired Aβ-degradation in presence of capsaicinoids is dependent on the insulin-degrading-enzyme, one of the major Aβ-degrading-enzymes. Regarding Aβ-homeostasis, no differences were found between the major capsaicinoids, capsaicin and dihydrocapsaicin, and a mixture of naturally derived capsaicinoids; effects on Ca2+-homeostasis were ruled out. Our results show that in respect to Alzheimer’s disease, besides the known positive effects of capsaicinoids, pro-amyloidogenic properties also exist, enhancing Aβ-levels, likely restricting the potential use of capsaicinoids as therapeutic substances in Alzheimer’s disease.

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The Impact of Cholesterol, DHA, and Sphingolipids on Alzheimer’s Disease

BioMed Research International ◽

10.1155/2013/814390 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 47

Author(s):

Marcus O. W. Grimm ◽

Valerie C. Zimmer ◽

Johannes Lehmann ◽

Heike S. Grimm ◽

Tobias Hartmann

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Proteolytic Processing ◽

Transgenic Mouse Models ◽

App Processing ◽

Amyloid A ◽

The Impact

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder currently affecting over 35 million people worldwide. Pathological hallmarks of AD are massive amyloidosis, extracellular senile plaques, and intracellular neurofibrillary tangles accompanied by an excessive loss of synapses. Major constituents of senile plaques are 40–42 amino acid long peptides termedβ-amyloid (Aβ). Aβis produced by sequential proteolytic processing of the amyloid precursor protein (APP). APP processing and Aβproduction have been one of the central scopes in AD research in the past. In the last years, lipids and lipid-related issues are more frequently discussed to contribute to the AD pathogenesis. This review summarizes lipid alterations found in ADpostmortembrains, AD transgenic mouse models, and the current understanding of how lipids influence the molecular mechanisms leading to AD and Aβgeneration, focusing especially on cholesterol, docosahexaenoic acid (DHA), and sphingolipids/glycosphingolipids.

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