RESEARCH

ROLE OF TAU NATIVE INTERACTORS ON TAU AMYLOIDOGENIC PROPERTIES AND DISEASE PATHOGENESIS

The Lasagna-Reeves Lab studies the role of different physiological partners of tau in its stabilization, accumulation, localization, folding, misfolding and toxicity. To pursue this, the lab combined in vitro structural and cellular techniques with mouse genetic and pharmacological manipulations to determine the effects of a specific interactor on tau toxicity in neurodegenerative tauopathies. This research strategy is suitable for tau and also applicable to the study of other neurodegenerative diseases characterized by toxic-protein aggregation.

FORMATION OF TAU PORE-LIKE STRUCTURES IN NEURODEGENERATIVE TAUOPATHIES

Annular protofibrils (APFs) represent a new and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. In previous studies, it was reported that tau and Aβ APFs are in a pathway distinct from fibril formation in vitro and in vivo. These findings establish the pathological significance of APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative diseases. Currently, the Lasagna-Reeves Lab is studying the role of tau in the plasma membrane and dissecting the mechanism of APFs formation.

ROLE OF TAU IN CEREBRAL AMYLOID ANGIOPATHY (CAA)

Cerebral amyloid angiopathy (CAA), is a condition where there’s a marked accumulation of amyloid in arterial walls. It occurs in over 85% of AD cases and is the hallmark of many other neurodegenerative diseases. Vascular accumulation of amyloids triggers a molecular cascade leading to tau accumulation, but unfortunately, there is no clear understanding of the molecular/cellular mechanisms that underlie the contribution of CAA to neurodegeneration and dementia. Therefore, our lab is focused on dissecting the mechanism(s) by which CAA leads to neuroinflammation, abnormal tau accumulation, and neurodegeneration.

TBI AND NEURODEGENERATIVE TAUOPATHIES

The long-term consequences of Traumatic brain injury (TBI) are multifaceted and include increased risk for Alzheimer’s disease (AD). To date, mechanisms linking TBI to AD remain unclear. Astrocytes are early responders to TBI and have an essential role in stimulating other cellular responses. Different forms of reactive astrocytes have a critical role in a variety of post-trauma mechanisms including regulation of inflammation and synaptic functions. The implication of astrocytic tau in neurodegenerative progression is unknown. Still, it has been shown that tau lesions impact astrocytes functions, leading to deleterious consequences within the astrocytes as well as effects on neuronal death. Studies suggest that tau pathology propagation is one of the mechanisms underlying the long-term neurodegenerative effects after TBI. The mechanism by how tau propagation in TBI subsequently triggers AD pathogenesis is still unknown. In our lab, we study how vascular damage triggered by TBI induces astrocytic-tau aggregation that subsequently promotes tau spreading throughout the brain eliciting synaptotoxicity and neurodegeneration as observed in AD and AD-related dementias.