Blocking cholesterol storage to treat Alzheimer’s disease

Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.

Download Full-text

Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

International Journal of Alzheimer s Disease ◽

10.4061/2011/956104 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Katsumi Matsuzaki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Physicochemical Properties ◽

Lipid Rafts ◽

Molecular Mechanisms ◽

Amyloid Fibrils ◽

Protein A ◽

Pivotal Role ◽

Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

Download Full-text

Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings

Science Translational Medicine ◽

10.1126/scitranslmed.aba1871 ◽

2020 ◽

Vol 12 (570) ◽

pp. eaba1871

Author(s):

Selene Lomoio ◽

Rachel Willen ◽

WonHee Kim ◽

Kevin Z. Ho ◽

Edward K. Robinson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variant ◽

Late Onset ◽

Early Stage ◽

Loss Of Function ◽

Axonal Trafficking ◽

Axonal Swellings

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

Download Full-text

Genes, pathways and risk prediction in Alzheimer’s disease

Human Molecular Genetics ◽

10.1093/hmg/ddz163 ◽

2019 ◽

Author(s):

John Hardy ◽

Valentina Escott-Price

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Membrane Damage ◽

Disease Process ◽

Complete Understanding ◽

Induced Membrane ◽

Genome Wide ◽

Key Factor ◽

Risk Of Disease

Abstract The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the disease process before overt symptoms occur. The rare, early onset forms of the disease are all caused by mutations which make amyloid deposition a more likely event. Here we discuss the recent data showing that, in contrast, much of the risk of late onset disease is encoded by loci involved in lipid metabolism and/or encoded by microglia. We discuss these finding and suggest that amyloid induced membrane damage may be a key factor in disease and also review the evidence that genome wide genetic analysis can substantially help in the prediction of those individuals at high risk of disease in the general population.

Download Full-text

[P3-338]: IN VIVO TAU PET IMAGING IN EARLY-ONSET ALZHEIMER's DISEASE AND LATE-ONSET ALZHEIMER's DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1553 ◽

2017 ◽

Vol 13 (7S_Part_22) ◽

pp. P1083-P1083

Author(s):

Young Noh ◽

Han Kyu Na ◽

Seongho Seo ◽

Sang-Yoon Lee ◽

Hye Jin Jeong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Early Onset ◽

Late Onset ◽

Early Onset Alzheimer’S Disease ◽

Tau Pet ◽

Tau Pet Imaging

Download Full-text

Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo.

10.1101/2021.03.19.436147 ◽

2021 ◽

Author(s):

Elena Simonazzi ◽

Ruth Jones ◽

Fangli Chen ◽

Adam Ranson ◽

Joshua Stevenson-Hoare ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Family ◽

Family Member ◽

Late Onset ◽

Gene Family Member ◽

Surveillance Activity ◽

Increased Risk ◽

Microglial Morphology

A rare coding variant of Abelson-interactor gene family member 3 (Abi3) is associated with increased risk of late-onset Alzheimer's Disease (AD). Although Abi3 is recognised as a core microglial gene, its role in microglia is largely unknown. Here we demonstrate that Abi3 is crucial for normal microglial morphology, distribution, and homeostatic tissue surveillance activity in vivo.

Download Full-text

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

10.21203/rs.3.rs-33900/v1 ◽

2020 ◽

Author(s):

Vaishnavi S. Jadhav ◽

Peter BC. Lin ◽

Guixiang Xu ◽

Taylor Pennington ◽

Gonzalo Viana Di Prisco ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Late Onset ◽

Synaptic Proteins ◽

Synaptic Protein ◽

Presenile Dementia ◽

Altered Expression ◽

Protein Levels

Abstract Background:Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and NasuHakola Disease (NHD). The Trem2 variantR47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linkedTrem2 variants like Y38Care associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2species predispose individuals to presenile dementia.Methods:To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function, we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38/Y38C and Trem2-/-mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results:While mice harboring Trem2 Y38C exhibited normal expression levels of Trem2, the pathological outcomes phenocopied Trem2-/- miceat 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion:Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38Cand Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like tau or amyloid. This suggests TREM2 impacts neuronal functions and providesmolecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Download Full-text

A Snapshot on the Current Status of Alzheimer’s Disease, Treatment Perspectives, in-Vitro and in-Vivo Research Studies and Future Opportunities

Chemical and Pharmaceutical Bulletin ◽

10.1248/cpb.c19-00511 ◽

2019 ◽

Vol 67 (10) ◽

pp. 1030-1041

Author(s):

Gizem Tezel ◽

Selin Seda Timur ◽

İsmail Bozkurt ◽

Ö. Faruk Türkoğlu ◽

İpek Eroğlu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Current Status ◽

Disease Treatment ◽

Research Studies

Download Full-text

Targeted Nanotherapy for Cognitive Impairment: Blocking Amyloid-β-Induced Membrane Damage in Brain Tissue

10.20944/preprints201808.0204.v1 ◽

2018 ◽

Author(s):

Joseph D'Arrigo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Subjects ◽

Membrane Damage ◽

Cell Types ◽

Cubic Phase ◽

Type I ◽

Co Morbidity ◽

Cns Penetration

A frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed over past decades. Accordingly, much evidence has been reported which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, obesity, diabetes, smoking, hypertension, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug, especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease (e.g., the anticancer drug bexarotene); this (candidate repurposing) drug up to now, by itself (i.e, without nanocarrier), displayed poor CNS penetration in human subjects.

Download Full-text

BIOBASED NANOEMULSION FOR BLOCKING COVID-19 FROM ACCELERATING ALZHEIMER'S DISEASE

Juvenis scientia ◽

10.32415/jscientia_2021_7_4_5-11 ◽

2021 ◽

Vol 7 (4) ◽

pp. 5-11

Author(s):

J. S. D'Arrigo

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Late Onset ◽

Cell Types ◽

Competitive Binding ◽

Amyloid A ◽

Lipid Nanocarriers ◽

Effective Therapeutic Strategy

An effective therapeutic strategy to delay dementia could be based upon nanotargeting drug(s), using lipid nanocarriers (i.e., biobased nanoemulsion technology), toward a major serum amyloid A (SAA) receptor responsible for certain proinflammatory, SAA-mediated, cell signaling events. For example, other investigators have already confirmed that SR-BI receptors (or its human ortholog CLA-1) function as proinflammatory cell-surface SAA receptors, and additionally report that various ligands for CLA-1/SR-BI "efficiently compete" with SAA for CLA-1/SR-BI binding. A similar benefit (of "competitive binding") may well accompany the clinical intravenous use of the ("HDL-like") lipid nanocarriers (i.e., biobased nanoemulsion [see above]), which have already been repeatedly described in the peer-reviewed literature as a targeted (and SR-BI mediated) drug-delivery agent. To conclude, the above-proposed "competitive binding", between SAA and such biobased nanoemulsion(s), could assist/enhance the protective (ordinarily anti-inflammatory) role of HDL - as well as provide targeted drug-delivery to the (human) brain cells bearing CLA-1/SR-BI receptors. The first resulting advantage is that this (intravenous) colloidal-nanocarrier therapeutic makes it possible for various cell types, all potentially implicated in Alzheimer's disease and/or (late-onset) dementia, to be simultaneously sought out and better reached for localized drug treatment of brain tissue in vivo. A second major advantage is that this therapeutic-target approach has particular relevance to the current COVID-19 human pandemic; namely, immune response and excessive inflammation in COVID-19 infection may accelerate the progression of brain inflammatory neurodegeneration which, if effectively halted, might play a major role in reducing Alzheimer's disease pathology.

Download Full-text

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Molecular Neurodegeneration ◽

10.1186/s13024-020-00409-0 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Vaishnavi S. Jadhav ◽

Peter B. C. Lin ◽

Taylor Pennington ◽

Gonzalo Viana Di Prisco ◽

Asha Jacob Jannu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Late Onset ◽

Synaptic Proteins ◽

Synaptic Protein ◽

Presenile Dementia ◽

Altered Expression ◽

Protein Levels

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Download Full-text