Browsing by Author "Lähteenmäki, Ida"

Alzheimer's disease is a progressive neurodegenerative disease of the central nervous system, in which accumulation of amyloid β plaques and hyperphosphorylated tau proteins cause neuronal death, loss of synapses, and impaired neurotransmission. Alzheimer's disease's main symptoms are memory dysfunction (dementia) and decline in cognition. One of the most significant factors believed to cause dementia in Alzheimer's disease is the destruction of dendritic spines. Dendritic spines are small protrusions of dendrites where most of the glutamatergic synapses are located and where mainly excitatory synaptic functions occur. Loss of dendritic spines is directly correlated to the loss of synaptic function, which then causes memory dysfunction and impaired cognition. Also, the morphology of dendritic spines is important for their stability and strength. The spine head's size is correlated to the number of postsynaptic receptors. Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are unconventional neurotrophic factors, which have neuroprotective and -restorative effects via regulating endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Accumulation of unfolded and/or misfolded proteins in the lumen of ER causes ER stress, which then activates UPR, which again maintains protein homeostasis by reducing the amount of unfolded/misfolded proteins. In this study, we injected CDNF, MANF or PBS into the hippocampus of C57BL/6 mice to analyze whether they increase dendritic spine density and improve their morphology, especially by increasing the density of mature spines. This study shows that MANF increases dendritic spine density and CDNF does not. MANF increases the density of most of the mature and immature spines but interestingly decreases the density of mature stubby spines. These results are very promising and MANF's effect on dendritic spine formation should be studied further. In another separate study, we investigated whether CDNF and MANF activate the ERK1/2 pathway on organotypic hippocampal slices. This pathway is important for memory formation, and another neurotrophic factor, brain-derived neurotrophic factor (BDNF), has been shown to increase dendritic spine density by stimulating the ERK1/2 pathway. CDNF and MANF activate UPR, but there is some evidence that UPR might also activate ERK1/2, which could then explain CDNF's and MANF's mechanism of action. CDNF and MANF-treated hippocampal slices had visually thicker and darker bands in ERK1/2 antibody staining but any conclusion cannot be made because of the sample sizes being too small.