Neurobiology of Memory //
Our research focus is in neurobiological mechanisms of memory loss in Alzheimer’s disease.
Research methods and approaches
- Our primary disease model is a transgenic mouse model carrying Swedish APP and Finnish PSEN1dE9 human gene mutations (Jankowsky J et al. Hum. Mol. Gen. 2004) that cause rare familial forms of AD. Among numerous AD model mice this line is different in that amyloid plaque pathology starts early (~3 months of age) and is fully developed before memory impairment becomes evident (~12 months of age). This order of events corresponds to present understanding of the disease course.
- Mouse neurological and neuropsychological testing. Through a broad behavioral test battery we can fully characterize the phenotype of AD mouse models and assess the effect of novel therapeutic approaches.
- In vivo electrophysiology. By using multiple bi- or tripolar implanted microelectrodes into areas of interest, we can assess long-term changes in local electrical activity at any brain site, as well as to study the cross-talk between these brain sites. Recordings are combined with video monitoring, also during a memory task. We also combine EEG recordings with BOLD-fMRI in mice.
- Histopathology. At the end of any study, the mouse brain is carefully examined for hallmarks of AD pathology (amyloid deposit, tau phosphorylation, neuroinflammation) and other processes of interest.
- Gene transfer. By using viral vectors we can transduce production of any protein of interest locally in the brain to study the molecular interactions behind the memory problems or to reverse the pathological process in a treatment attempt.
- Pre-clinical assessment of novel treatments including conventional drug candidates or dietary manipulations.
- We have carefully characterized the brain distribution of amyloid accumulation in a typical APP/PS1 mouse model and demonstrated impaired hippocampal-dependent spatial memory but intact striatal-dependent response habit learning in APP/PS1 mice.
- We were the first to show that amyloid accumulation is faster in female than in male APP/PS1 transgenic mice.
- We were the first to show that the latest AD drug memantine has beneficial cognitive effects in a transgenic AD mouse model.
- We were the first to show that hippocampal CA3 area becomes hyperactive in aged rats and perturbs the balance in the hippocampal neural network, a finding that has recently been confirmed in MCI patients
- We were the second lab in the world to report that APP transgenic mice display frequent seizures and the only one that has conducted a systematic study on the prevalence of epilepsy in a large APP/PS1 mouse cohort.
- We have demonstrated that memory impairment in APP/PS1 mice depends on the BDNF signaling through its TrkB receptor and that long-memory can be augmented by the recently discovered neurotrophin CDNF.
- We have demonstrated that manipulation of dietary lipids has a major impact on cognitive functions in APP/PS1 mice.
- Contribution of epileptic spiking to fluctuating memory impairment in AD
- Changes in functional connectivity between brain areas in APP/PS1 mice
- Role of brain lymphatic vessels in early amyloid pathology (A Finnish consortium)
- Early amyloid pathology in the entorhinal cortex (A Nordic consortium)
- Novel diagnostic and therapeutic methods to target tau pathology (EU H2020 consortium)
- Koivisto H, Leinonen H , Puurula M, Hafez HS, Alquicer Barrera G, Stridh MH, Waagepetersen HS, Tiainen M, Soininen P, Zilberter Y, Tanila H. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice. Front Aging Neurosci 2016; 8: 41.
- Kemppainen S, Lindholm P, Galli E, Lahtinen HM, Koivisto H, Hämäläinen E, Saarma M, Tanila H. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice. Behav Brain Res. 2015;291:1-11.
- Koivisto H, Grimm MO, Rothhaar TL, Berkecz R, Lütjohann D D, Giniatullina R, Takalo M, Miettinen PO, Lahtinen HM, Giniatullin R, Penke B, Janáky T, Broersen LM, Hartmann T, Tanila H. Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition. J Nutr Biochem. 2014;25(2):157-69.
- Gurevicius K, Lipponen A, Tanila H. Increased cortical and thalamic excitability in freely moving APPswe/PS1dE9 mice modeling epileptic activity associated with Alzheimer’s disease. Cerebral Cortex 2013;23(5):1148-58.
- Kemppainen S, Rantamäki T, Jerónimo-Santos A, Lavasseur G, Autio H, Karpova N, Kärkkäinen E, Stavén S, Vicente Miranda H, Outeiro TF, Diógenes MJ, Laroche S,Davis S, Sebastião AM, Castrén E, Tanila H. Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. Neurobiol Aging. 2012 Jun;33(6):1122.e23-39.
- Hiltunen M, Khandelwal VK, Yaluri N, Tiilikainen T, Tusa M, Koivisto H, Krzisch M, Vepsäläinen S, Mäkinen P, Kemppainen S, Miettinen P, Haapasalo A, Soininen H, Laakso M, Tanila H. Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice. J Cell Mol Med. 2012;16(6):1206-22.
- Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B, Zilberter Y, Harkany T, Pitkänen A, Tanila H. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009 Mar 18;29(11):3453-62.
- Wilson IA, Gallagher M, Eichenbaum H, Tanila H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci. 2006 Dec;29(12):662-70.
- Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci. 2005 Jul 20;25(29):6877-86.
- Minkeviciene R, Banerjee P, Tanila H. Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther. 2004 Nov;311(2):677-82.