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Area of Science:

  • Neuroscience
  • Aging Research
  • Animal Models

Background:

  • TDP43 and Alpha-synuclein (αsyn) are increasingly linked to Alzheimer's disease (AD) and AD-related dementias (ADRD).
  • Understanding mixed pathologies in AD requires appropriate animal models, with marmosets emerging as a valuable system due to translational limitations of rodent models.
  • Previous work established tau isoform expression in marmosets, setting the stage for investigating other key proteins.

Purpose of the Study:

  • To analyze the age-related spontaneous expression of TDP43 and αsyn in the marmoset brain.
  • To investigate the interaction of TDP43/αsyn pathology with Aβ/Tau pathology in genetically modified marmosets (PSEN1 mutations) and those with induced tau pathology (p301Ltau).

Main Methods:

  • Western Blot (WB) and immunohistochemistry (IHC) were used to analyze TDP43 and αsyn expression and subcellular localization in marmoset brain tissues.
  • Tissues from marmosets with PSEN1 mutations and those seeded with AAV p301Ltau were used to examine Aβ/Tau pathology interactions.
  • ELISA was employed to measure brain TDP43 and plasma Aβ and total Tau.

Main Results:

  • TDP43 and αsyn were found to be expressed in both nuclear and cytosolic fractions across various age groups of marmosets.
  • No significant age-related alterations in TDP43 and αsyn expression were observed in the studied marmoset cohort.
  • Ongoing studies are evaluating TDP43 and αsyn pathologies in aged, PSEN1 mutant, and tau-seeded marmosets.

Conclusions:

  • The study confirms the presence and subcellular distribution of TDP43 and αsyn proteins in the marmoset brain.
  • Marmoset models are crucial for studying the natural progression of mixed pathologies relevant to aging and ADRD.
  • These findings support the utility of marmosets in understanding the association between mixed pathologies and cognitive decline.