Browsing by Subject "Amyloid"

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  • Lindgren, Noora; Kaprio, Jaakko; Karjalainen, Tomi; Ekblad, Laura; Helin, Semi; Karrasch, Mira; Teuho, Jarmo; Rinne, Juha O.; Vuoksimaa, Eero (2021)
    We studied the association between episodic memory and cortical fibrillar β-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([11C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [11C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions.
  • Prebble, Dale W; Voser, Vanja; Er, Safak; Hlushchuk, Irena; Domanskyi, Andrii; Airavaara, Mikko; Ekins, Merrick G; Mellick, George D; Carroll, Anthony R (2022)
    During a high-throughput screen of 300 Australian marine invertebrate extracts, the extract of the marine sponge Clathria (Thalysias) cf. hesperia was identified with α-synuclein binding activity. The bioassay-guided purification of this extract resulted in the isolation of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2) as the α-syn binder along with one new compound, hesperine (1), and five known compounds, indole-3-carboxaldehyde (3), (Z)-2'-demethylaplysinopsin (4), 2-amino-4'-hydroxyacetophenone (5), 4-hydroxybenzoic acid (6) and 4-hydroxybenzaldehyde (7). Herein, we report the structure elucidation of hesperine (1) and α-syn binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2).
  • Brunello, Cecilia A.; Merezhko, Maria; Uronen, Riikka-Liisa; Huttunen, Henri J. (2020)
    Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer’s disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.
  • Jäntti, Henna; Sitnikova, Valeriia; Ishchenko, Yevheniia; Shakirzyanova, Anastasia; Giudice, Luca; Ugidos, Irene F.; Gomez-Budia, Mireia; Korvenlaita, Nea; Ohtonen, Sohvi; Belaya, Irina; Fazaludeen, Feroze; Mikhailov, Nikita; Gotkiewicz, Maria; Ketola, Kirsi; Lehtonen, Sarka; Koistinaho, Jari; Kanninen, Katja M.; Hernandez, Damian; Pebay, Alice; Giugno, Rosalba; Korhonen, Paula; Giniatullin, Rashid; Malm, Tarja (2022)
    Background Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (A beta) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of A beta. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored. Methods Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and A beta pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations. Results We show that PIEZO1 orchestrates A beta clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. A beta inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in A beta clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets. Conclusion These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated A beta burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.
  • Strandberg, Timo; Koivisto, Anne (2022)
  • Ylikoski, Ari; Partinen, Markku (2017)
    Unettomuuden lisääntyminen ja yöunen rikkonaisuus ovat tavallisia sekä ikääntymiseen että ¬neurodegeneraatioon liittyviä vaivoja. Ihmisen ikääntyessä useat välittäjäaineet vähenevät, kuten myös hermosolut erityisesti sinitumakkeessa ja hypotalamuksen tumakkeissa. Kohorttitutkimuksissa on havaittu, että unihäiriöt edeltävät usein neurodegeneratiivisten sairauksien tyypillisiä ydinoireita. Uuden tutkimustiedon mukaan unihäiriöt voivat altistaa neurodegeneratiivisille sairauksille ja pahentaa niitä. Unihäiriöt kuuluvat näiden sairauksien hoidettavissa oleviin riskitekijöihin. Uni tai sen puute saattavat suojata neurodegeneraatiolta tai altistaa sille usealla eri mekanismilla.
  • Auvinen, Petri; Scheperjans, Filip (2016)
    Tutkimusmenetelmien kehittyminen on avannut elimistömme mikrobistosta tutkimuslinjoja mm. neurodegeneratiivisiin ­sairauksiin. Suomessa on tehty hiljattain ensimmäiset havainnot Parkinson-potilaiden suolistomikrobiomin poikkeavasta ­koostumuksesta.