21st Young Neuroscientist Meeting

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Presentation transcript:

21st Young Neuroscientist Meeting Zagreb, 29th June 2017 The blood-brain barrier: a novel target for treatment of Alzheimer's disease Mirjana Babić Leko, PhD Croatian Institute for Brain Research University of Zagreb School of Medicine Croatian Science Foundation

Campbell-Switzer-Martin method Bielschowsky silver staining Šimić et al., Prog. Neurobiol., 2017.

CAA in AD brain leads to dysfunction of bloodbrain barrier (BBB) Amyloid β peptide (Aβ) accumulates in the walls of cerebral arteries, arterioles, capillaries and veins The prevalence of cerebral amyloid angiopathy (CAA) in patients with AD varies from 70–100% CAA in AD brain leads to dysfunction of bloodbrain barrier (BBB) Zlokovic, Neuron, 2008.

Therapeutic effect in AD was achieved by opening of the BBB BBB was transiently opened with repeated scanning ultrasound (SUS) in APP23 transgenic mouse model of AD After the treatment, Aβ and plaque load was reduced and mice had improvement in memory (assessed by tests of spatial and recognition memory) Leinenga and Gotz, Sci. Transl. Med., 2015.

CSF analysis of 103 subjects (63 AD, 30 MCI, 10 HC) for 24 macro- and microelements using ICP-MS (inductively-coupled plasma mass spectrometry) and 6 protein AD biomarkers: Aβ1-42 (Innotest β-amyloid1-42, Fujirebio, Gent, Belgium) Total tau (Innotest hTau Ag, Fujirebio, Gent, Belgium) p-tau181 (Innotest Phospho-Tau(181P), Fujirebio, Gent, Belgium) p-tau199 (TAU [pS199] Phospho-ELISA Kit, Human, Thermo Fisher Scientific, Waltham, MA, USA) p-tau231 (Tau [pT231] Phospho-ELISA Kit, Human, Thermo Fisher Scientific, Waltham, MA, USA) VILIP-1 (Human ELISA, BioVendor, Brno, Czech Republic)

Macro- and microelements in cerebrospinal fluid 24 macro and microelements neither showed diagnostic potential for early detection of AD, nor correlated with cognitive impairment in the patients with AD (measured by MMSE) Comparison of macro- and microelements measured in CSF between Alzheimer’s disease (AD), mild cognitive impairment (MCI) patients and healthy controls (HC)

Comparison of macro- and microelements measured in CSF between Alzheimer’s disease (AD), mild cognitive impairment (MCI) patients and healthy controls (HC)

Correlation with Aβ1-42 and total tau CSF macro- and microelements showed good correlation with CSF protein biomarkers of AD (Aβ1-42, total tau, p-tau181, p-tau199, p-tau231 and VILIP-1) Correlation with Aβ1-42 and total tau

Correlation with p-tau181

Correlation with p-tau199

Correlation with p-tau231

Correlation with VILIP-1

p-tau181 and p-tau199

p-tau231, p-tau181 and Aβ1-42

VILIP-1 and Aβ1-42

Se, Tl, Zn, Cr, Ba - were significantly associated with 6 biomarkers Cu, Fe, As, Co, Ca, Mg, S - were significantly associated with 5 biomarkers Hg, Mn, K, Sr i Na - were significantly associated with 4 biomarkers Cd, Ni, Mo, B - were significantly associated with 3 biomarkers Al, Pb - were significantly associated with 2 biomarkers Li - was significantly associated with only 1 biomarker

Correlation of macro- and microelements with CSF protein biomarkers

This study showed good correlation of analysed macro- and microelements with p-tau181, p-tau199 and p-tau231, and especially the levels of VILIP-1 protein Is the association of these macro- and microelements with protein biomarkers of AD the consequence of interaction between macro- and microelements and either phospho-tau isoforms or VILIP-1 in CSF, the result of pathological processes in AD or the result of both processes?

The scope of our future studies: Measurement of 24 macro- and microelements in plasma of AD, MCI patients and HCs Testing of BBB permeability by the measurement of albumin ratio in plasma and CSF, the ratio of neurofilament light polypeptide in plasma and CSF and concentration of S-100β protein in plasma of AD and MCI patients and HCs

Collaborators Croatian Science Foundation Goran Šimić, Danira Bažadona, Vesna Benković, Fran Borovečki, Domagoj Đikić, Maja Jazvinšćak Jembrek, Željka Petelin Gadže, Nada Oršolić Jasna Jurasović, PhD Tatjana Orct, PhD Institute for Medical Research and Occupational Health, Zagreb, Croatia Croatian Science Foundation IP-2014-09-9730 (2015-2019)