Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

Aging, tau pathology, and chronic inflammation in the brain play crucial roles in synaptic loss, neurodegeneration, and cognitive decline in tauopathies, including Alzheimer's disease. Senescent cells accumulate in the aging brain, accelerate the aging process, and promote tauopathy progression through their abnormal inflammatory secretome known as the senescence-associated secretory phenotype (SASP). Tau oligomers (TauO)—the most neurotoxic tau species—are known to induce senescence and the SASP, which subsequently promote neuropathology, inflammation, oxidative stress, synaptic dysfunction, neuronal death, and cognitive dysfunction. TauO, brain inflammation, and senescence are associated with heterogeneity in tauopathy progression and cognitive decline. However, the underlying mechanisms driving the disease heterogeneity remain largely unknown, impeding the development of therapies for tauopathies. Based on clinical and preclinical evidence, this review highlights the critical role of TauO and senescence in neurodegeneration. We discuss key knowledge gaps and potential strategies for targeting senescence and TauO to treat tauopathies. Highlights: Senescence, oligomeric Tau (TauO), and brain inflammation accelerate the aging process and promote the progression of tauopathies, including Alzheimer's disease. We discuss their role in contributing to heterogeneity in tauopathy and cognitive decline. We highlight strategies to target senescence and TauO to treat tauopathies while addressing key knowledge gaps.

Original languageEnglish (US)
Pages (from-to)709-727
Number of pages19
JournalAlzheimer's and Dementia
Volume20
Issue number1
DOIs
StatePublished - Jan 2024
Externally publishedYes

Keywords

  • Alzheimer's disease
  • aging
  • cognitive deficits
  • inflammation
  • senescence-associated secretory phenotype
  • senescent cells
  • tau
  • tauopathies

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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