The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

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Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22116071 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6071

Author(s):

Suzanne Gascon ◽

Jessica Jann ◽

Chloé Langlois-Blais ◽

Mélanie Plourde ◽

Christine Lavoie ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Growth Factors ◽

Signaling Pathways ◽

Brain Structures ◽

Therapeutic Strategies ◽

Native Proteins ◽

Receptor Sites ◽

The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

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Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Aβ peptides in animal model of Alzheimer’s disease

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.11.043 ◽

2019 ◽

Vol 110 ◽

pp. 47-58 ◽

Cited By ~ 18

Author(s):

Syed Obaidur Rahman ◽

Bibhu Prasad Panda ◽

Suhel Parvez ◽

Madhu Kaundal ◽

Salman Hussain ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Animal Model ◽

Aβ Peptides ◽

Model Of Alzheimer’S Disease

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The emerging role of β-secretases in cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01953-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Francesco Farris ◽

Vittoria Matafora ◽

Angela Bachi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Poor Prognosis ◽

Cancer Development ◽

Ectodomain Shedding ◽

Research Groups ◽

Aβ Peptides ◽

Tumor Types

AbstractBACE1 and BACE2 belong to a class of proteases called β-secretases involved in ectodomain shedding of different transmembrane substrates. These enzymes have been extensively studied in Alzheimer's disease as they are responsible for the processing of APP in neurotoxic Aβ peptides. These proteases, especially BACE2, are overexpressed in tumors and correlate with poor prognosis. Recently, different research groups tried to address the role of BACE1 and 2 in cancer development and progression. In this review, we summarize the latest findings on β-secretases in cancer, highlighting the mechanisms that build the rationale to propose inhibitors of these proteins as a new line of treatment for different tumor types.

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Getting to NO Alzheimer’s Disease: Neuroprotection versus Neurotoxicity Mediated by Nitric Oxide

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3806157 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 54

Author(s):

Rachelle Balez ◽

Lezanne Ooi

Keyword(s):

Nitric Oxide ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Neuronal Excitability ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Protective Role ◽

Ionic Mechanisms

Alzheimer’s disease (AD) is a neurodegenerative disorder involving the loss of neurons in the brain which leads to progressive memory loss and behavioral changes. To date, there are only limited medications for AD and no known cure. Nitric oxide (NO) has long been considered part of the neurotoxic insult caused by neuroinflammation in the Alzheimer’s brain. However, focusing on early developments, prior to the appearance of cognitive symptoms, is changing that perception. This has highlighted a compensatory, neuroprotective role for NO that protects synapses by increasing neuronal excitability. A potential mechanism for augmentation of excitability by NO is via modulation of voltage-gated potassium channel activity (Kv7 and Kv2). Identification of the ionic mechanisms and signaling pathways that mediate this protection is an important next step for the field. Harnessing the protective role of NO and related signaling pathways could provide a therapeutic avenue that prevents synapse loss early in disease.

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Autophagy in Alzheimer’s disease pathogenesis: therapeutic potential and future perspectives

10.22541/au.160825175.58383447/v1 ◽

2020 ◽

Author(s):

Zhigang Zhang ◽

You-Qiang Song ◽

Jie Tu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

The Elderly ◽

Future Perspectives ◽

Aβ Peptides ◽

Evolutionarily Conserved ◽

Amyloid Aβ ◽

Folded Proteins

Alzheimer’s disease (AD) is a complex neurodegenerative disease in the elderly. It is the most common cause of dementia in human. AD is characterized by accumulation of abnormal protein aggregates including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Besides, synaptic plasticity, neuroinflammation, calcium signaling etc. are found to be dysfunctional as well in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to the modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has showed that impaired autophagy contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategy in AD therapeutics.

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Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

Journal of Personalized Medicine ◽

10.3390/jpm10040221 ◽

2020 ◽

Vol 10 (4) ◽

pp. 221 ◽

Cited By ~ 1

Author(s):

Eleonora Del Prete ◽

Maria Francesca Beatino ◽

Nicole Campese ◽

Linda Giampietri ◽

Gabriele Siciliano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Plasma Biomarker ◽

Clinical Role ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Aβ Peptides ◽

The Brain

A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments.

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The Role of Aβ in the Development of Alzheimer’s Disease and its Mechanisms

E3S Web of Conferences ◽

10.1051/e3sconf/202021803041 ◽

2020 ◽

Vol 218 ◽

pp. 03041

Author(s):

Yifei Jin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Elderly Population ◽

Clinical Symptoms ◽

Senile Plaques ◽

The Elderly ◽

Aβ Peptides ◽

Hyperphosphorylated Tau Protein ◽

Neurodegenerative Dementia

Alzheimer’s disease (AD) is chronic neurodegenerative dementia representing the most common cause of dementia in the elderly population. It is a major source of morbidity, mortality, and healthcare expenditure worldwide. Although the molecular and cellular properties related to AD have been demonstrated decades before the onset of clinical symptoms, AD’s pathogenesis is still unknown as a combination of risk factors causes it. Today, pathogenesis theories focused on senile plaques (SP) formed by the extracellular accumulation and deposition of Aβ peptides and neurofibrillary tangles (NFTs), which are composed of the hyperphosphorylated tau protein. Furthermore, growing evidence points out that toxic Aβ plays a primary causal role in the induction and transmission of pathology and neuronal dysfunction and loss. Therefore, Aβ is crucial to the development of AD and is a noteworthy issue in AD research. This review shows the formation of Aβ and the differences of cytotoxicity of its various isoforms and aggregation states. It also summarizes the mechanisms by which Aβ induce AD through its neurotoxicity and state how these mechanisms interact and reinforce each other.

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