Alzheimer’s disease (AD) is the most common form of dementia affecting up to 50% of individuals above the age of 85. Its global financial burden is expected to reach 2 trillion US $ by year 2030 (World AD Report 2015). Despite the decades of research, treatment options are very limited. There have been 200 negative trials during the last 30 years. Pharmacological research has mainly focused on decreasing amyloid plaque pathology without paying a sufficient attention to improving metabolic functions of glia. Large genome-wide association studies have implicated glia in AD pathogenesis, with most risk genes (APOE, TREM2, CD33, ABI3, PLCG2 etc.) being expressed predominantly in microglia and / or astrocytes.
In our laboratory, we have recently demonstrated that astrocytes carrying early-onset AD-associated mutation in PSEN1 gene display a severe metabolic dysfunction (Oksanen, et al. 2017). This dysfunction can be ameliorated by sulforaphane treatment through the upregulation of Nrf2 pathway (Oksanen, et al. 2020). In addition to published PSEN1 mutant iPSC lines, we have human iPSC lines carrying Swedish mutation in APP gene, lines carrying a protective A673T (Icelandic) APP mutation, and lines from sporadic AD patients.
In collaboration with Dr. Mikko Hiltunen (University of Eastern Finland, Kuopio, Finland) we are a part of The EU’s Joint Programme – Neurodegenerative Disease Research (JPND)-funded project Personalized medicine approach for novel microglia-associated genetic variants in Alzheimer’s disease (PMG-AD). As part of this project, we have generated several new iPSC lines carrying risk variant in ABI3 gene (S209F), their control lines and ABI3 knockout lines. We are further working on generating microglia from these iPSC lines. The purpose of the project is to determine whether AD-associated risk variants cause functional deficits in microglia contributing to AD pathology and whether these deficits could be ameliorated by drug treatment.
We have also crossed an AD transgenic mouse strain overproducing beta-amyloid (APPSwe x PSEN1 dE9) with an immunedeficient mouse strain carrying a human version of CSF1, a key growth factor needed for microglial survival. This mouse strain supports survival and proliferation of the transplanted human microglia and allows for studying the effect of microglia-expressed genetic risk variants on amyloid pathology.
We are also interested in pathological changes caused by AD-associated genetic risk variants in cells forming the blood-brain barrier. We have recently developed a protocol for the generation of iPSC-derived pericytes, and are developing 3D culture models combining human iPSC-derived astrocytes, endothelial cells, and pericytes. Finally, we are part of ENTRAIN project with the focus on interaction of endothelial cells with macrophages.
Schizophrenia (SCZ) affects 20 million people worldwide, and 55-65,000 people from the Finnish population (Skitsofrenia, Käypähoito –suositus, 2020). Symptoms as hallucinations and delusions manifest at early adolescence, but the first biological changes in brain functions appear already during pregnancy. Despite the strong heritability, the monozygotic twin has only 50% risk to develop SCZ when the co-twin has been diagnosed with the disorder. We have generated iPSC lines from five monozygotic twin pairs, who are discordant to SCZ, in this collaboration with Prof. Jari Tiihonen (Niuvanniemi Hospital, Kuopio, Finland; Karolinska Institutet, Stockholm, Sweden, and visiting scientist in Neuroscience center at HiLIFE, University of Helsinki).
Several neuronal and glial cell type dysfunctions have been identified in patients with SCZ. In our first study, we generated cortical neurons from twin cell lines and discovered sex-specific gene expression changes and SCZ-related altered pathways (Tiihonen, et al. 2019b). Also, affected twins showed altered NMDA and GABA calcium responses which were normalized with antipsychotic drug clozapine. Later we showed similar results with astrocyte cultures (Koskuvi, et al. 2021). Affected astrocyte progenitors were also transplanted into mouse brain and resulted in behavioral changes in cognitive and olfactory functions.
In collaboration with group leader Olli Pietiläinen (University of Helsinki, Helsinki, Finland), we study NGN2-neuron maturation in human astrocyte co-cultures and electrophysiological properties in SCZ neuronal cultures.
Psychopathy is a disorder characterized by a loosely correlated set of interpersonal, affective, and behavioral features including pronounced emotional deficits such as diminished sense of guilt and empathy. Psychopathy also involves an increased risk for antisocial behavior and poor impulse control. Although psychopaths represent less than 1% of the general population and 15-25% of prison populations, they perpetrate even 30–50% of all violent crimes. The heritability of severe antisocial behavior is up to 50 %, but the genetic background of psychopathy is unclear.
In collaboration with Prof. Jari Tiihonen (Niuvanniemi Hospital, Kuopio, Finland; Karolinska Institutet, Stockholm, Sweden, Neuroscience center, HiLIFE, University of Helsinki, Finland), we have generated human iPSC lines from psychopathic violent substance abusers and healthy controls and substance abusers without psychiatric manifestations. This project aims to bring new insight into the neurobiological features of severe antisocial behavior and psychopathy. Using hiPSC-derived cortical neurons and astrocytes we have identified several gene expressional changes related to immune response, opioid receptor function, insulin sensitivity and glucose metabolism (Tiihonen et al. 2019a). In the future, we focus on how our genetic findings affect neuronal functionality and opioid receptor system in psychopathic neuronal cultures.
Sex differences have been acknowledged in brain structure as in behavior. During fetal and neonatal development both genetic and sex hormones have been suggested to influence human sex differences of the brain and less-studied sexual orientation. Current evidence in imaging studies associate that same-sex sexual behavior-related differences in brain structural differences in gray matter volumes, especially in thalamic and hypothalamic regions (Votinov, et al. 2021). The previous research from Ganna et al. (2019) has shown that same-sex sexual behavior is influenced by several genetic variants, which explained 8-25 % of variation in same-sex sexual behavior. In this study, together with Prof. Jari Tiihonen (Niuvanniemi Hospital, Kuopio, Finland; Karolinska Institutet, Stockholm, Sweden; Neuroscience center, HiLIFE, University of Helsinki, Finland) and Dr. Markku Lähteenvuo (Niuvanniemi Hospital, Kuopio, Finland) we investigate expressional differences in neuronal cultures derived either from individuals who reported opposite-sex behavior and individuals who reported same-sex behavior to address the question of neurobiological origin of sexual orientation.
Parkinson’s disease (PD) is considered to arise from the degeneration of dopaminergic neurons in substantia nigra and decreased release of dopamine in striatum, which causes tremor, rigidity and bradykinesia in patients. While studies have focused on dopaminergic neurons, contribution of astrocytes and microglia to PD pathology has been investigated only sparsely.
We collaborate with group leader Sarka Lehtonen (University of Eastern Finland, Kuopio, Finland, also a member of our team) to investigate glial cell contribution to PD pathology. In our previous study, astrocytes derived from LRRK2 mutant patients manifested several PD hallmarks including increased production of α-synuclein, increased response to inflammation, mitochondrial defects and altered polyamine metabolism (Sonninen, et al. 2020).