Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein

Gomes, Luis Aragão; Hipp, Silvia Andrea; Upadhaya, Ajeet Rijal; Karthikeyan, B.; Ospitalieri, Simona; Koper, Marta J.; Largo-Barrientos, Pablo; Uytterhoeven, Valerie; Reichwald, Julia; Rabe, Sabine; Vandenberghe, Rik; Arnim, Christine A. F. Von; Tousseyn, Thomas; Feederle, Regina; Giudici, Camilla; Willem, Michael; Staufenbiel, Matthias; Thal, Dietmar Rudolf

doi:10.1007/s00401-019-02053-5

Cited by 84 publications

(76 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mouse primary neurons (MPNs) and induced neurons (iNs) seeded in clear bottom, black wall 96-well plates (#655090; Greiner Bio-One, Monroe, NC) were immunostained using a modified serial-permeabilized protocol [33]. All buffers and reagents were prepared fresh and 0.22 µm filtered prior to use.…”

Section: Immunocytochemistry and Quantificationmentioning

confidence: 99%

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

et al. 2019

View full text Add to dashboard Cite

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plateimmobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrP C. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

show abstract

Section: Immunocytochemistry and Quantificationmentioning

confidence: 99%

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

et al. 2019

View full text Add to dashboard Cite

show abstract

“…**Significant differences compared to age-matched controls P < 0.01. c Correlation between brain EV proteomes and MHC class-derived proteins identified in preclinical AD 9631 proteins from all analyzed conditions (Supplementary Data Set 1). To obtain a visual representation of this complex and large dataset and to categorize identified brain EV proteins according to their abundances and distribution along the AD course, we performed fuzzy c-mean clustering as previously described [2,3]. A total of 10 clusters containing 332 proteins on average were obtained, from which three showed distinctive and remarkable patterns (Supplementary Figure 2 and Supplementary Data Set 2).…”

Section: Clustering Analysis Of Brain Ev Proteomes In Ad Reveals Archmentioning

confidence: 99%

“…Alzheimer's disease (AD) is the largest global contributor to cognitive decline and dementia [1]. AD-diseased brains tend to accumulate senile plaques and neurofibrillary tangles in the temporal and neocortical regions, which are mainly formed by fibrillar amyloid-β (Aβ peptide) and hyperphosphorylated Tau, respectively [2].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles

et al. 2020

View full text Add to dashboard Cite

Background: The contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer's disease (AD) remain poorly understood. Methods: Here, we investigated the role(s) of brain EV in the progressive course of AD through unbiased proteome-wide analyses of temporal lobe-derived EV and proteome-label quantitation of complementary remaining brain portions. Furthermore, relevant proteins identified were further screened by multiple reaction monitoring. Results: Our data indicate that EV biogenesis was altered during preclinical AD with the genesis of a specific population of EV containing MHC class-type markers. The significant presence of the prion protein PrP was also manifested in these brain vesicles during preclinical AD. Similarly, sequestration of amyloid protein APP in brain EV coincided with the observed PrP patterns. In contrast, active incorporation of the mitophagy protein GABARAP in these brain vesicles was disrupted as AD progressed. Likewise, disrupted incorporation of LAMP1 in brain EV was evident from the initial manifestation of AD clinical symptoms, although the levels of the protein remained significantly upregulated in the temporal lobe of diseased brains. Conclusions: Our findings indicate that impaired autophagy in preclinical AD coincides with the appearance of proinflammatory and neuropathological features in brain extracellular vesicles, facts that moderately remain throughout the entire AD progression. Thus, these data highlight the significance of brain EV in the establishment of AD neuropathology and represent a further leap toward therapeutic interventions with these vesicles in human dementias.

show abstract

“…The abnormal accumulations of Aβ and tau proteins are pathological hallmarks of AD and contribute to the neurodegenerative process in the brains of patients with AD. Although tau deposition was considered a downstream event in the Aβ hypothesis, increasing evidence indicated that Aβ and tau protein accumulations lead to neurotoxicity in parallel (Gomes et al, 2019). Previous studies have identified that three pathogenic genes (APP, PSEN1, and PSEN2) are involved in the pathogenesis of EOAD, suggesting the significant role of Aβ metabolism in EOAD (Jiao et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Association of Genes Involved in the Metabolic Pathways of Amyloid-β and Tau Proteins With Sporadic Late-Onset Alzheimer’s Disease in the Southern Han Chinese Population

Xiao

Jiao

Liao

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

The genes involved in the metabolic pathways of amyloid-β (Aβ) and tau proteins significantly influence the etiology of Alzheimer's disease (AD). Various studies have explored the associations between some of these genes and AD in the Caucasian population; however, researches regarding these associations remain limited in the Chinese population. To systematically evaluate the associations of these genes with AD, we investigated 19 genes involved in the metabolism of Aβ and tau based on previous studies selected using the PubMed database. This study included 372 patients with sporadic late-onset AD (sLOAD) and 345 cognitively healthy individuals from southern China. The results were replicated in the International Genomics of Alzheimer's Project (IGAP). Protein-protein interactions were determined using the STRING v11 database. We found that a single-nucleotide polymorphism, rs11682128, of BIN1 conferred susceptibility to sLOAD after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {corrected P = 0.000153, odds ratio (OR) [95% confidence interval (CI)] = 1.403 (1.079-1.824)}, which was replicated in the IGAP. Protein-protein interactions indicated that BIN1 was correlated with MAPT. Moreover, rare variants of NEP and FERMT2 (0.0026 < corrected P < 0.05), and the Aβ degradation, tau pathology, and tau phosphatase pathways (0.01 < corrected P < 0.05), were nominally significantly associated with sLOAD. This study suggested that the genes involved in the metabolic pathways of Aβ and tau contributed to the etiology of sLOAD in the southern Han Chinese population.

show abstract

Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein

Cited by 84 publications

References 104 publications

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles

Association of Genes Involved in the Metabolic Pathways of Amyloid-β and Tau Proteins With Sporadic Late-Onset Alzheimer’s Disease in the Southern Han Chinese Population

Contact Info

Product

Resources

About