Alzheimer: A Complex Genetic Background

Abstract We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

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A lipid-invasion model for Alzheimer’s Disease

10.7287/peerj.preprints.27811v5 ◽

2019 ◽

Author(s):

Jonathan D Rudge

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Principal Role ◽

Lipid Droplet Formation ◽

Invasion Model ◽

Β Amyloid ◽

Mass Influx ◽

The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

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A lipid-invasion model for Alzheimer’s Disease

10.7287/peerj.preprints.27811 ◽

2019 ◽

Author(s):

Jonathan D Rudge

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Principal Role ◽

Lipid Droplet Formation ◽

Invasion Model ◽

Β Amyloid ◽

Mass Influx ◽

The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

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Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

Cells ◽

10.3390/cells9112347 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2347

Author(s):

Anna Atlante ◽

Giuseppina Amadoro ◽

Antonella Bobba ◽

Valentina Latina

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Food Product ◽

Neuroprotective Effects ◽

The Road ◽

Beneficial Effects ◽

Β Amyloid ◽

The Brain

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.

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Central 5-HTR2C in the Control of Metabolic Homeostasis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.694204 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ting Yao ◽

Jiehui He ◽

Zhicheng Cui ◽

Ruwen Wang ◽

Kaixuan Bao ◽

...

Keyword(s):

Glucose Metabolism ◽

Metabolic Regulation ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Molecular Pathways ◽

Metabolic Hormones ◽

Obesity Drugs ◽

G Protein Coupled ◽

The Brain

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

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A lipid-leakage model for Alzheimer’s Disease

10.7287/peerj.preprints.27811v2 ◽

2019 ◽

Author(s):

Jonathan D Rudge

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fatty Acids ◽

Anterograde Amnesia ◽

Principal Role ◽

Leakage Model ◽

Β Amyloid ◽

Mass Influx ◽

The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid leakage model. It proposes that AD is caused by the influx of lipids following the breakdown of the blood brain barrier (BBB).The model argues that a principle role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD, especially FFAs, which stimulate microglia-driven neuroinflammation, inhibit neurogenesis and cause endosomal-lysosomal abnormalities, all characteristic of AD. In most cases amyloidosis and tau tangle formation lie downstream of these lipids and are in many ways as much symptomatic of the disease as causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that anterograde amnesia is far more pronounced in AD than ARBD results from the greater hydrophobicity of FFAs, in an anaesthesia-related manner.

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Bacterial Extracellular DNA Promotes β-amyloid Aggregation

10.20944/preprints202105.0556.v1 ◽

2021 ◽

Author(s):

George Tetz ◽

Victor Tetz

Keyword(s):

Protein Misfolding ◽

Mechanisms Of Action ◽

Extracellular Dna ◽

Pathogenic Role ◽

Bacterial Dna ◽

Beta Peptide ◽

Β Amyloid ◽

The Brain

Alzheimer’s disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer’s disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer’s disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer’s disease.

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The Role of Irisin in Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm7110407 ◽

2018 ◽

Vol 7 (11) ◽

pp. 407 ◽

Cited By ~ 9

Author(s):

Oh Kim ◽

Juhyun Song

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Background ◽

Senile Plaques ◽

Metabolic Dysfunction ◽

Lipid Imbalance ◽

The Relationship ◽

The Brain

Alzheimer’s disease (AD) is characterized by progressive memory dysfunction, oxidative stress, and presence of senile plaques formed by amyloid beta (A β ) accumulation in the brain. AD is one of the most important causes of morbidity and mortality worldwide. AD has a variety of risk factors, including environmental factors, metabolic dysfunction, and genetic background. Recent research has highlighted the relationship between AD and systemic metabolic changes such as glucose and lipid imbalance and insulin resistance. Irisin, a myokine closely linked to exercise, has been associated with glucose metabolism, insulin sensitivity, and fat browning. Recent studies have suggested that irisin is involved in the process in central nervous system (CNS) such as neurogenesis and has reported the effects of irisin on AD as one of the neurodegenerative disease. Here, we review the roles of irisin with respect to AD and suggest that irisin highlight therapeutic important roles in AD. Thus, we propose that irisin could be a potential future target for ameliorating AD pathology and preventing AD onset.

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A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

10.1101/766089 ◽

2019 ◽

Cited By ~ 1

Author(s):

Thomas M Piers ◽

Katharina Cosker ◽

Anna Mallach ◽

Gabriel Thomas Johnson ◽

Rita Guerreiro ◽

...

Keyword(s):

Immune Cell ◽

Loss Of Function ◽

Human Patient ◽

Metabolic Switch ◽

Risk Variant ◽

Β Amyloid ◽

Human Ipsc ◽

Plastic Responses ◽

The Brain

AbstractLoss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.

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A lipid-leakage model for Alzheimer’s Disease

10.7287/peerj.preprints.27811v3 ◽

2019 ◽

Author(s):

Jonathan D Rudge

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Principal Role ◽

Leakage Model ◽

Lipid Droplet Formation ◽

Β Amyloid ◽

Mass Influx ◽

The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-leakage model. It proposes that AD is caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principle role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-leakage model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that best accounts for all currently known major risk factors, and credibly explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that have been too readily overlooked by other accounts of this disease.

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