The goal of the Experimental Dementia Research Unit is to contribute to new biological insights that will help in the development of therapeutic strategies against the major neurodegenerative diseases of aging that cause dementia.
Building on prior neuropathology and neuroscience research
Our group focuses on the pathophysiological mechanisms by which synapses are sites of early dysfunction and damage in the most common neurodegenerative disease causing dementia, Alzheimer’s disease (AD).
Our work took a different direction from the mainstream of AD research that focused on extracellular β-amyloid (Aβ) peptides with our discovery of the accumulation of Aβ within AD vulnerable neurons of human brains (Gouras et al., 2000). Following this work, we were the 1st group to report on the physical association between altered AD-linked Aβ peptides and synapses in the brain, showing that Aβ preferentially accumulates and associates with subcellular pathology within distal neurites and synapses in AD (Takahashi et al., 2002; 2004; Capetillo-Zarate et al., 2011). Using dual-immuno-electron microscopy we further showed that early tau alterations initiate in Aβ accumulating synaptic terminals in the brain (Takahashi et al., 2010) providing the first physical link between Aβ and initiation of tau alterations at synapses. We were also the first group to use primary neurons from AD transgenic mice to model Aβ accumulation in culture (Takahashi et al., 2004) and subsequently to report on selective Aβ dependent alterations in synaptic proteins and neurotransmitter receptors, including surface glutamate receptors and PSD-95 (Almeida et al., 2005). A major effort of our group has been to determine the cell biological mechanism(s) by which Aβ peptides initiate dysfunction of synapses in AD. We provided evidence for Aβ-dependent dysfunction in the ubiquitin proteasome system and multivesicular body (MVB) sorting pathway (Almeida et al., 2006). Moreover, we carried out studies on the mechanism whereby β-amyloid antibodies can reduce Aβ peptides and protect synapses in cellular models of AD, providing a biological mechanism for a leading therapeutic direction for AD: Aβ immunotherapy (Tampellini et al., 2007); this work provided novel findings that antibodies can act within neurons after internalization. In addition, we provided insights into Aβ modulation of the mTOR pathway, a central signaling pathway that is implicated in aging, synaptic plasticity and autophagy (Ma et al., 2010). A particular emphasis for our group has been to better understand how synaptic activity modulates the pathophysiology of synapse damage in AD. We reported that synaptic activity reduces the intraneuronal pool of Aβ (Tampellini et al., 2009). Remarkably, reduced synaptic activity in vivo in the brain (using either the whisker – barrel cortex system or treatment with benzodiazepine) reduced amyloid plaques but still damaged synapses, providing experimental evidence for a disconnect between amyloid plaques and Aβ -mediated synapse damage in AD (Tampellini et al., 2010). In addition, we provided novel evidence indicating that Aβ secretion is reduced with AD (Tampellini et al., 2011) and the first cellular model of Aβ prion-like propagation (Olsson et al., 2018). For our most comprehensive review on intraneuronal Aβ, see Gouras GK et al., ACTA Neuropathol, 2010. For a review focused on therapy, see Gouras et al., Neurotherapeutics, 2015.
- Elucidate the cell biological mechanisms whereby proteins/peptides specifically linked with neurodegenerative dementias cause synaptic dysfunction using primary neuron culture models of neurodegenerative diseases; emphasis is on Aβ, apoE and tau. Further, the interaction of astrocytes and microglia with synapses is of growing interest in our group
- Studies on the mechanisms whereby synaptic activity modulates synaptic damage in neurodegenerative dementias using cellular and mouse models
- Characterize the early neuropathology of neurodegenerative diseases causing dementias
- Develop improved treatment strategies for Alzheimer’s disease and related disorders by protecting against the synapse damage that characterizes these neurodegenerative dementias