Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes

151

153

Background: Cerebrospinal fluid Tau levels are altered in tauopathies; however, the mechanism of Tau secretion is poorly understood. Results: Tau isoforms and mutations alter extracellular Tau levels in cultured cells. Conclusion: Tau is actively released, and Tau release is modified by variability in Tau that is associated with tauopathies. Significance: Defining factors that influence Tau release is crucial to understanding Tau metabolism in tauopathies.

Section: Discussionmentioning

confidence: 99%

Extracellular Tau Levels Are Influenced by Variability in Tau That Is Associated with Tauopathies

Karch

Jeng

Goate

2012

151

153

“…Conversely, intracellular aggregates might destabilize membranes to create transient rupture, or they might be released upon cell death or axon degeneration. Although much contention exists with regard to mechanisms of Tau secretion (52,53,(73)(74)(75)(76)(77), a recent study on SOD1 aggregates suggests a dual mode of aggregate release. Under this paradigm, healthy cells release SOD1 into the medium in association with exosomes, whereas dying cells release free aggregates (78).…”

Section: Understanding Cell Uptakementioning

confidence: 99%

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Holmes

Diamond

2014

171

133

Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and ␣-synuclein, can propagate aggregates between cells in a prionlike manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.Neurodegenerative diseases account for an enormous human and financial cost to our society, estimated in excess of $200 billion annually (1). Despite decades of study, there is no disease-modifying therapy. Virtually all neurodegenerative diseases are associated with the accumulation of fibrillar protein aggregates, and all are relentlessly progressive. There is now abundant evidence for an association of neuronal networks with patterns of spread through the brain (2-4). Studies of relatively rare, dominantly inherited neurodegenerative diseases have indicated that proteins that accumulate in sporadic forms of disease, such as prion protein, Tau, ␣-synuclein, and TDP-43, also cause pathology in the setting of destabilizing point mutations (5-8). This provides a strong indication that protein aggregation is itself a proximal cause of disease and is not simply an epiphenomenon. Indeed, protein aggregation is the most unifying pathological feature of adult onset neurodegenerative disorders. The proximal initiators of protein aggregation likely vary among different proteins and cell types, whereas the accumulation of misfolded species in general appears to be linked to the age-dependent breakdown of cellular quality control pathways (9, 10). It is not understood, however, why neurodegenerative diseases are relentlessly progressive or why they involve neural networks (3,11,12). A variety of studies are consistent with the idea that mechanisms similar to those of propagation of prion pathology could underlie disease progression. Prion protein (PrP c ) 2 is a normal cellular protein that can be converted to a disease-causing conformation (PrP Sc ) through interaction with a pathogenic prion protein "seed." The conversion mechanism is not fully understood, but involves templated conformational change, whereby a PrP Sc seed contacts natively folded protein and induces it to assemble onto a growing aggregate. PrP Sc aggregates can have multiple conformations, each linked to unique pathological patterns (13-15), and they have been demonstrated in experimental systems to propagate through neural networks (16). Thus, the prion hypothesis provides a useful model by which to test ideas about propagation of protein pathology in other neurodegenerative diseases. Prion-...

“…The internalization of PrpSc aggregates has been reported in murine and human neuroblastoma cell lines and mouse fibroblasts, whereby heparan sulfates and lipid rafts turned out to be involved (1, 34 -37). SOD1 aggregates are internalized by macropinocytosis by N2a cells, a neuroblastoma cell line (8), whereas Tau aggregates were taken up by HEK-293 cells and neuroblastoma cell lines (6,38,39). Currently, it is not known whether different amyloids share common pathways of internalization.…”

mentioning

confidence: 99%

Sequence-dependent Internalization of Aggregating Peptides

Couceiro

Gallardo

Smet

et al. 2015

Background: Prionoid propagation requires cell internalization of aggregated polypeptides. Results: Aggregates of different sequence are internalized through different endocytic pathways. Only phagocytosed aggregates (Ͼ1 m) elicit an HSF1-dependent proteostatic response. Conclusion: Proteostatic response upon aggregate internalization differs markedly depending on the sequence. Significance: The characterization of mechanisms of cell penetration is fundamental for the understanding of aggregate transmission in disease.