Visiting Investigators

Permanent URI for this collection

https://hdl.handle.net/1912/116

Scores of distinguished biologists from around the world come to the MBL to collaborate and conduct research. They use marine and other organisms as model systems for their research.

These researchers participate in a number of established MBL groups including but not limited to:

  • MBL Summer Research Fellows
  • Dart Scholars
  • Grass Faculty Awardees
  • NeuroImaging Cluster
  • Grass Fellows
  • Whitman Center

Browse

Browsing Visiting Investigators by Subject "Alzheimer's disease"
  • Preprint
    The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity
    ( 2008-04) LaPointe, Nichole E. ; Morfini, Gerardo A. ; Pigino, Gustavo F. ; Gaisina, Irina N. ; Kozikowski, Alan P. ; Binder, Lester I. ; Brady, Scott T.
    The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent FAT rates evaluated by video microscopy. While perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
  • Article
    Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition
    (Elsevier, 2016-07-29) Cox, Kristine ; Combs, Benjamin ; Abdelmesih, Brenda ; Morfini, Gerardo A. ; Brady, Scott T. ; Kanaan, Nicholas M.
    Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.
  • Article
    Frontotemporal lobar dementia mutant tau impairs axonal transport through a protein phosphatase 1γ-dependent mechanism
    (Society for Neuroscience, 2021-10-04) Combs, Benjamin ; Christensen, Kyle R. ; Richards, Collin ; Kneynsberg, Andrew ; Mueller, Rebecca L. ; Morris, Sarah L. ; Morfini, Gerardo A. ; Brady, Scott T. ; Kanaan, Nicholas M.
    Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, β, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons.