Mechanistic approaches to understand the prion-like propagation of aggregates of the human tau protein

Kumar, Harish; Udgaonkar, Jayant B.

doi:10.1016/j.bbapap.2019.04.004

Cited by 8 publications

(10 citation statements)

References 159 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, Tau aggregation is inhibited by augmented autophagy [55], and ADNP/ NAP accelerate autophagy [14,15,19,[56][57][58][59]. As tauopathy is suggested to propagate in a prion-like manner [60][61][62], it is hypothesized that even rare occurrences of cellular tauopathy will propagate, making prevention therapy with NAP treatment prior to disease onset a desired possibility. More generally, recent findings show that the retrovirus-like Gag protein Arc1 binds RNA and traffics across synaptic buttons, suggesting the possibility of wide transfer of mutated disease driving RNAs [63].…”

Section: Discussionmentioning

confidence: 99%

“…In conclusion, we revealed somatic aging/AD-linked mutations converging on tauopathy [ 70 ], including NAP/ADNP [ 25 ]. We further showed a significant correlation between the frequency of the ADNP c.2187_2188insA mutation and aging, suggesting accumulation with aging and increasing Braak stages, implicating either a parallel or a causal relation, possibly linked to Tau-like prion-like propagation [ 60 – 62 ]. Together, our results represent a paradigm-shifting concept in the perception of AD, whereby accumulating somatic gene mutations promote brain pathology and cognitive loss, and open new horizons for research and development.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

et al. 2019

View full text Add to dashboard Cite

With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, humanized tau models with/without A␤-amyloidosis are advantageous resources for the study of pathological tau propagation. Tau protein resembles prion protein in its ability to propagate (30). The common underlying mechanisms likely involve conformational changes caused by the pathogenic forms as templates (31).…”

Section: Humanization Of Murine Mapt Genementioning

confidence: 99%

Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

Saito

Mihira

Matsuba

et al. 2019

Journal of Biological Chemistry

128

160

View full text Add to dashboard Cite

“…The application of tau aggregates from brains with AD can cause tau pathology in the injection sites and anatomically link brain regions. In vitro experiments have shown that incubation of recombinant tau with heparin can produce tau pathology, similar to the tau pathology propagation in the AD brain [12][13][14] . Prionlike propagation of tau pathology colaborates to the AD evolution [15] .…”

mentioning

confidence: 88%

Tau in Alzheimer’s Disease: Pathological Alterations and an Attractive Therapeutic Target

Liu

2020

CURR MED SCI

View full text Add to dashboard Cite

SummaryAlzheimer’s disease (AD) is an age-related neurodegenerative disease with two major hallmarks: extracellular amyloid plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. The number of NFTs correlates positively with the severity of dementia in AD patients. However, there is still no efficient therapy available for AD treatment and prevention so far. A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades. Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD. Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders. Abnormal tau hyperphosphorylation plays a detrimental pathological role, eventually leading to neurodegeneration. In the present review, we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

show abstract

Mechanistic approaches to understand the prion-like propagation of aggregates of the human tau protein

Cited by 8 publications

References 159 publications

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

Tau in Alzheimer’s Disease: Pathological Alterations and an Attractive Therapeutic Target

Contact Info

Product

Resources

About