scholarly journals APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brain

2020 ◽  
Author(s):  
Tomàs Jordà-Siquier ◽  
Melina Petrel ◽  
Vladimir Kouskoff ◽  
Fabrice Cordelières ◽  
Susanne Frykman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Dense Core ◽  
Subcellular Compartment ◽  
Aβ Peptides ◽  
Synaptic Markers ◽  
Analytical Tools ◽  
Presynaptic Proteins

SummaryIn Alzheimer’s disease (AD), a central role is given to the extracellular deposition of Aβ peptides, remotely produced by the proteolysis of the amyloid precursor protein (APP). This contrasts with other neurodegenerative diseases which are characterized by the intraneuronal aggregation of full-length proteins such as huntingtin, α-synuclein or TDP-43. Importantly, the distribution of APP around amyloid plaques is poorly characterized. Here, we combined an extensive set of methodological and analytical tools to investigate neuropathological features of APP in the human AD hippocampus and in two mouse models of AD. We report that APP remarkably accumulates in the surrounding of dense-core amyloid plaques together with the secretases necessary to produce Aβ peptides. In addition, the Nter domain, but not the Cter domain of APP is enriched in the core of amyloid plaques uncovering a potential pathological role of the secreted APP-Nter in dense-core plaques. To investigate the subcellular compartment in which APP accumulates, we labelled neuritic and synaptic markers and report an enrichment in presynaptic proteins (Syt1, VAMP2) and phosphorylated-Tau. Ultrastructural analysis of APP accumulations reveals abundant multivesicular bodies containing presynaptic vesicles proteins and autophagosomal built-up of APP. Altogether, our data supports a role of presynaptic APP in AD pathology and highlights APP accumulations as a potential source of Aβ and Nter peptides to fuel amyloid plaques.

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

2018 ◽  
Vol 15 (13) ◽  
pp. 1191-1212 ◽  
Author(s):  
Botond Penke ◽  
Gábor Paragi ◽  
János Gera ◽  
Róbert Berkecz ◽  
Zsolt Kovács ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Membrane Lipids ◽  
Specific Protein ◽  
Dietary Factors ◽  
Lipid Signaling ◽  
Special Role ◽  
Aβ Peptides

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.

scholarly journals Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

2021 ◽  
Author(s):  
Rolando Oyola ◽  
Deguo Du ◽  
Idalia Ramos ◽  
Kyabeth Torres ◽  
Ambar S Delgado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptides ◽  
Gallium Nanoparticles

Alzheimer’s disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to...

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

2019 ◽  
Vol 110 ◽  
pp. 47-58 ◽  
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

scholarly journals The emerging role of β-secretases in cancer

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.

scholarly journals Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Tomasz Jaworski ◽  
Sebastian Kügler ◽  
Fred Van Leuven
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Amyloid Plaques ◽  
Amyloid Peptides ◽  
Alois Alzheimer ◽  
Second Shift ◽  
Amyloid Cascade

Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the “concrete” deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions.

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

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.

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

2020 ◽  
Vol 10 (4) ◽  
pp. 221 ◽  
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.

scholarly journals Therapeutic Potential of Neu1 in Alzheimer’s Disease Via the Immune System

2021 ◽  
Vol 36 ◽  
pp. 153331752199614
Author(s):  
Aiza Khan ◽  
Sumit Das ◽  
Consolato Sergi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Therapeutic Potential ◽  
Amyloid Plaques ◽  
Beta Amyloid ◽  
Underlying Mechanism ◽  
Amyloid Deposits ◽  
Potential Therapeutic Role

Alzheimer’s Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.

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