| 1. |
- Agholme, Lotta, et al.
(författare)
-
Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
- 2014
-
Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 58, s. 29-39
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.
|
|
| 2. |
- Domert, Jakob, et al.
(författare)
-
Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
- 2014
-
Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 65, s. 82-92
-
Tidskriftsartikel (refereegranskat)abstract
- The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.
|
|
| 3. |
- Hallbeck, Martin, et al.
(författare)
-
Neuron-to-Neuron Transmission of Neurodegenerative Pathology
- 2013
-
Ingår i: The Neuroscientist. - : Sage Publications. - 1073-8584 .- 1089-4098. ; 19:6, s. 560-566
-
Forskningsöversikt (refereegranskat)abstract
- One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.
|
|
| 4. |
- Nath, Sangeeta, et al.
(författare)
-
Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid
- 2012
-
Ingår i: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 32:26, s. 8767-8777
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.
|
|
