Gunnar Keppler GourasProfessor, Directly Appointed, Professor of Experimental Neurology
Research areas and keywords
UKÄ subject classification
- Medical and Health Sciences
- Alzheimer's disease, Dementia, Neurodegenerative diseases, Ageing, Parkinson's disease
Experimental Dementia Research
Dementia defines a category of diseases characterized by progressive and debilitating decline in cognitive functions. The major causes of dementia are neurodegenerative diseases of aging, including Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia. In addition, vascular disease is an important cause and contributor.
Dementia is a major and growing public health concern as the number of patients and the associated health care costs continue to rise. Alzheimer’s disease is the leading cause of dementia. Currently, there are no treatments known to halt or slow the progression of this disease in afflicted individuals.
In the Experimental Dementia Research Unit we work to uncover the cell biological and pathological basis of dementia, with a focus on Alzheimer’s disease. We provided the first evidence that age-related dysfunction in Alzheimer’s disease initiates with aberrant accumulation and aggregation of β-amyloid peptides within vulnerable neurons, in particular their terminals. The goal of our research is to provide biological and therapeutic insights that will help in the development of more effective new therapies for dementia.
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 main stream 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 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). 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 among others, aging and synaptic plasticity (Ma et al., 2010).
A particular emphasis is to better understand how synaptic activity modulates the pathophysiology of synapse damage in models of 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 elevated intraneuronal Aβ and 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).
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
- 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
- Gouras GK, Olsson TT, Hansson O.β-amyloid Peptides and Amyloid Plaques in Alzheimer's Disease. Neurotherapeutics. 2014 Nov 5. [Epub ahead of print]
- Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E. Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. ACTA Neuropathologica, 119(5):523-41, 2010.
Recent research outputs
Research output: Contribution to journal › Debate/Note/Editorial
Research output: Contribution to journal › Article
Research output: Contribution to journal › Article