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/Lewy Body dementia and frontotemporal dementia. In addition, vascular disease is an important cause and contributor of dementia.

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. Treatments have long been unable to slow the progression of dementia in afflicted individuals. However, recent approvals for immunotjerapy for Alzheimer's disease are giving new hope.

In the Experimental Dementia Research Unit we work to uncover the cell biological and pathological basis of dementias, with a focus on Alzheimer’s disease. We provided the first evidence that age-related pathology in Alzheimer’s disease initiates with aberrant accumulation and aggregation of β-amyloid peptides within vulnerable neurons, in particular their neurite terminals (Takahashi RH et al., 2002). The aim of our research team is to provide biological and therapeutic insights that will help in the development of more effective new therapies for dementia.

The overall goal of the Experimental Dementia Research Unit in Lund 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

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 synapses in AD (Takahashi et al., 2002; 2004; Capetillo-Zarate et al., 2011). Using dual-immuno-electron microscopy we further dicovered 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 the multivesicular body (MVB) sorting pathway (Almeida et al., 2006). Moreover, we carried out studies on the cellular mechanisms whereby β-amyloid antibodies can reduce Aβ peptides and protect synapses in cell 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 T et al., 2010).

A particular emphasis in our group then turned to better understanding 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).

More recently, we carried out studies on the prion-like properties of Aβ. In Olsson et al., 2018 and then in a comprehensive study in ACTA Neuropathologica (Roos et al., 2021) we provided novel insights into the importance of intraneuronal Aβ in prion-like spread. We believe that a challenge with ongoing approaches on immunotherapy for AD is that the focus has been on extracellular amyloid plaques rather than the actual pathological damage occurring within neurons, which lead eventually to extracellular plaques as we modelled experimentally in papers Willén K et al., 2017 (Molecular Neurodegeneration) and more recently in Roos et al., 2021.

Current work has tunred to a focus on the neurobiology of ApoE4 and the view that the synaptic endosome is a pivotal site of early AD where amyloid, apoE and tau intersect. Growing interest in our group is the role of lipids in early AD biology and pathology of synaptic endosomes of vulnerable neurons.

Ongoing projects

1. Elucidate the cell biological mechanisms whereby proteins/peptides specifically linked with neurodegenerative dementias cause synaptic dysfunction using primary neuron culture models, with an emphasis on the cellular convergence of Aβ, ApoE and tau in Alzheimer's disease.
2. Studies on the mechanisms whereby synaptic activity modulates synaptic damage in Alzheimer's disease using cellular and mouse models
3. To provide new insights to improve on treatment strategies for Alzheimer’s disease and related disorders by protecting against the early synapse and endosome alterations that characterize this neurodegenerative dementia.

Selected publications from the past few years:

Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer's Disease.

Martinsson I, Quintino L, Garcia MG, Konings SC, Torres-Garcia L, Svanbergsson A, Stange O, England R, Deierborg T, Li JY, Lundberg C, Gouras GK. Front Aging Neurosci. 2022 Jul 6;14:946297. doi: 10.3389/fnagi.2022.946297. PMID: 35928998

Astrocytic and Neuronal Apolipoprotein E Isoforms Differentially Affect Neuronal Excitability.

Konings SC, Torres-Garcia L, Martinsson I, Gouras GK. Front Neurosci. 2021 Sep 21;15:734001. doi: 10.3389/fnins.2021.734001. eCollection 2021.PMID: 34621153 

Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis.

Roos TT, Garcia MG, Martinsson I, Mabrouk R, Israelsson B, Deierborg T, Kobro-Flatmoen A, Tanila H, Gouras GK. Acta Neuropathol. 2021 Oct;142(4):669-687. doi: 10.1007/s00401-021-02345-9. Epub 2021 Jul 16.PMID: 34272583 

Selected older publications from our group:

APP depletion alters selective pre- and post-synaptic proteins.

Martinsson I, Capetillo-Zarate E, Faideau M, Willén K, Esteras N, Frykman S, Tjernberg LO, Gouras GK. Mol Cell Neurosci. 2019 Mar;95:86-95. doi: 10.1016/j.mcn.2019.02.003. Epub 2019 Feb 11.PMID: 30763689 

Prion-like seeding and nucleation of intracellular amyloid-β.

Olsson TT, Klementieva O, Gouras GK. Neurobiol Dis. 2018 May;113:1-10. doi: 10.1016/j.nbd.2018.01.015. Epub 2018 Feb 4.PMID: 29414379

Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

Willén K, Edgar JR, Hasegawa T, Tanaka N, Futter CE, Gouras GK. Mol Neurodegener. 2017 Aug 23;12(1):61. doi: 10.1186/s13024-017-0203-y.PMID: 28835279 

Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP.

Klementieva O, Willén K, Martinsson I, Israelsson B, Engdahl A, Cladera J, Uvdal P, Gouras GK. Nat Commun. 2017 Mar 13;8:14726. doi: 10.1038/ncomms14726.PMID: 28287086 

High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils.

Capetillo-Zarate E, Gracia L, Yu F, Banfelder JR, Lin MT, Tampellini D, Gouras GK. Am J Pathol. 2011 Nov;179(5):2551-8. doi: 10.1016/j.ajpath.2011.07.045. Epub 2011 Sep 15.PMID: 21925470 

Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice.

Tampellini D, Capetillo-Zarate E, Dumont M, Huang Z, Yu F, Lin MT, Gouras GK. J Neurosci. 2010 Oct 27;30(43):14299-304. doi: 10.1523/JNEUROSCI.3383-10.2010.PMID: 20980585 

Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations.

Tampellini D, Rahman N, Gallo EF, Huang Z, Dumont M, Capetillo-Zarate E, Ma T, Zheng R, Lu B, Nanus DM, Lin MT, Gouras GK. J Neurosci. 2009 Aug 5;29(31):9704-13. doi: 10.1523/JNEUROSCI.2292-09.2009.PMID: 19657023

Co-occurrence of Alzheimer's disease ß-amyloid and τ pathologies at synapses.

Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK. Neurobiol Aging. 2010 Jul;31(7):1145-52. doi: 10.1016/j.neurobiolaging.2008.07.021. Epub 2008 Sep 3.PMID: 18771816 

Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations.

Tampellini D, Magrané J, Takahashi RH, Li F, Lin MT, Almeida CG, Gouras GK. J Biol Chem. 2007 Jun 29;282(26):18895-906. doi: 10.1074/jbc.M700373200. Epub 2007 Apr 27.PMID: 17468102 

Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system.

Almeida CG, Takahashi RH, Gouras GK. J Neurosci. 2006 Apr 19;26(16):4277-88. doi: 10.1523/JNEUROSCI.5078-05.2006.PMID: 16624948 

Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.

Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK. Neurobiol Dis. 2005 Nov;20(2):187-98. doi: 10.1016/j.nbd.2005.02.008.PMID: 16242627

Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain.

Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK. J Neurosci. 2004 Apr 7;24(14):3592-9. doi: 10.1523/JNEUROSCI.5167-03.2004.PMID: 15071107 

Intraneuronal Alzheimer Abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.

Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK. Am J Pathol. 2002 Nov;161(5):1869-79. doi: 10.1016/s0002-9440(10)64463-x.PMID: 12414533 

Intraneuronal Abeta42 accumulation in human brain.

Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR. Am J Pathol. 2000 Jan;156(1):15-20. doi: 10.1016/s0002-9440(10)64700-1.PMID: 10623648