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conferenceseries
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Volume 8
Journal of Palliative Care & Medicine
ISSN: 2165-7386
Geriatrics 2018
July 30-31, 2018
July 30-31, 2018 | Barcelona, Spain
8
th
International Conference on
Geriatrics Gerontology & Palliative Nursing
Tau protein aggregation induces cellular senescence in the brain
Miranda E. Orr
South Texas Veterans Health Care System, USA
Statement of the Problem:
Tau protein accumulation is the most common pathology among degenerative brain diseases,
including Alzheimer’s disease, progressive supranuclear palsy, chronic traumatic encephalopathy and over twenty others1.
Mechanisms mediating tau toxicity are not well understood resulting in few treatment options and poor patient prognosis.
Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss. NFT-
containing neurons do not die, which suggests secondary mechanisms are driving toxicity.
Methodology &Theoretical Orientation:
We evaluated gene expression patterns of NFT-containing neurons microdissected
from Alzheimer’s disease patient brains, brain tissue from patients with supranuclear palsy and four independent Alzheimer’s
disease mouse models. The tau transgenic Alzheimer’s disease mouse models were treated with a well-characterized
pharmacological approach to remove senescent cells. The effects of drug treatment on tau pathology, brain structure and
function were determined with careful histology and brain MRI analyses.
Findings:
Neurons with NFTs from human Alzheimer’s disease brain develop an expression profile consistent with cellular
senescence. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular
remodeling, and metabolic dysfunction. Moreover, senescent cells induce chronic degeneration of surrounding tissue through
the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP).
Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype
including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of
senescence, directly correlated with brain atrophy and NFT load. We found this relationship extended to postmortem brain
tissue from humans with progressive supranuclear palsy to indicate a phenomenon common to tau toxicity. Treatment of tau
transgenic mice with drugs to remove senescent cells had decreased NFT burden, preserved neuronal and glial brain cells and
improved brain structure and function.
Conclusion & Significance:
Collectively, these findings indicate that NFTs induce cellular senescence in the brain, which
contributes to neurodegeneration and brain dysfunction. Moreover, removing senescent cells offers a new therapeutic approach
for the dozens of neurodegenerative diseases arising from pathogenic tau accumulation. Given the prevalence of tau protein
deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially
treating, dozens of brain diseases.
orrm3@uthscsa.eduJ Palliat Care Med 2018, Volume 8
DOI: 10.4172/2165-7386-C2-018