TGF-ß1 pathway as a new pharmacological target for neuroprotection in AD. Filippo Caraci

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1 Department of Clinical and Molecular Biomedicine Section of Pharmacology and Biochemistry Department of Educational Sciences University of Catania TGF-ß1 pathway as a new pharmacological target for neuroprotection in AD Filippo Caraci Valencia September

2 At the diagnostic stage Alzheimer s Disease presents a devastating brain pathology.too late for disease-modifying drugs? Aβ amyloid plaques Neurofibrillary tangles (NFT) P-Tau Human brain shrinks with age, shrinkage accelerated in Alzheimer s..

3 The Amyloid Cascade Hypothesis Revised APP Ab 1-42 production The loss of function hypothesis physiological pathological Early synaptic dysfunction Ab 1-42 monomers Ab 1-42 oligomers Loss of neuroprotective activity plaques Cell cycle activation Altered kinase activities tangles Neuronal death

4 Aß(1-42) monomers are neuroprotective via IGF-signaling

5 The Amyloid Cascade Hypothesis Revised APP Ab 1-42 production The loss of function hypothesis physiological pathological Early synaptic dysfunction Ab 1-42 monomers Ab 1-42 oligomers Loss of neuroprotective activity plaques Cell cycle activation Altered kinase activities tangles Neuronal death

6 The cell cycle hypothesis of AD APP and PS mutations AD neurons by T. Arendt, 2003 Ab Regulatory failure G0 G1 Post-mitotic neuron p21 p27 DNA replication S Functional impairment CDK1 Up to 1 year M G2 Tau hyperphosphorylation Neurodegeneration

7 DNA Replication Preceds Neuronal Cell Death in Alzheimer s Disease (K. Herrup s lab. 2001, 2006) FISH in human AD brain adult R1.40 mouse brain

8 Percentages of immunopositive neurons stained with cell cycle markers in the hippocampus The mechanism of cell loss (a cell cycle-induced death) and the rate of cell loss (a slow atrophy over several months) can be observed in an early phase of AD pathogenesis

9 from: Hoozemans et al., 2006

10 Biomarker model in the preclinical stage of Alzheimer s disease Latent, preclinical stage Cell cycle Activation Modified from Jack Jr et al, Lancet 2010

11 TGF-ß1 is a neurotrophic factor which may inhibit cell cycle activation through the induction of CDK inhibitors Low PH & Proteases # TGF-ß1 interacts with a high-affinity transmembrane receptor # complex consisting of the activin-like kinase 5 (ALK5)/TGF-ß type I receptor and the TGF-ß type II receptor (TßRII) subunits Smaddependent signaling Smad-independent signaling Akhurst and Hata 2012 Nature Drug Discovery

12 J. Clin. Invest. 116: (2006).

13 Hippocampus Can the reduced function of TGF-ß1 signaling contribute to activation of the cell cycle in AD brain?

14 Dysfunction of TGF-β1 signaling in AD pathogenesis Caraci and Copani JTR 2012

15 Inhibition of TGF-ß1 receptors amplifies Aß toxicity in the rat hippocampus Ve h icle S B PBS A ß (1-4 2 ) Aβ (1-42) Stereological infusion Caraci et al. 2008

16 Smad-independent TGF-ß1 signaling: crosstalk with other signaling pathways Akhurst and Hata 2012 Nature Drug Discovery

17 TGF-ß1 protects in the early and late phase of Aß toxicity

18 TGF-ß1 prevented Aß-induced neuronal S phase # Caraci et al Neurobiology of disease 30:234-42

19 TGF-ß1 activates the PI-3-Kinase pathway and rescues the Wnt pathway in Aß-treated neurons

20 Dual mechanism for TGF-b1-induced neuroprotection against Aβ-neurotoxicity

21 Which strategies to rescue TGF-ß1 signaling in AD brain? 1) Intracerebral delivery of neurotrophic factors cannot be considered as a suitable approach for treatment of AD patients; 2) Small chemical compounds that mimic TGF-β1 signaling are currently studied for the treatment of AD; 3) A more feasible approach might be the use of centrally available drugs which are able to increase the local production of TGF-β1

22 Potential pharmacological approaches to rescue neurotrophin signaling in AD Caraci & Drago Eur J Pharmacology 2010

23 Which molecular mechanisms are involved in the prevention of dementia by lithium?

24 Lithium induces the production and the release of TGF-β1 in rat cortical astrocytes Ctrl Lithium1mM 24h 300 Ctrl Lithium 1mM 24h TGF-b1/loading control * TGF-b1 (pgml) * 0 0 Pro-TGF-β1 Levels of the active form of TGF-β1 In ECM from rat cortical astrocytes as assessed by ELISA assay Caraci e al CNS Neuroscience

25 Lithium protects cultured cortical neurons against Aß toxicity via TGF-ß1 release

26 Agonists of group II metabotropic glutamate (mglu) receptors enhance the production of TGF-ß1 in cultures astrocytes Bruno et al. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J Neurosci Dec 1;18(23):

27 LY day trial vs. olanzapine and vs. placebo

28 Psychosis of Alzheimer s disease (PAD) First patient described by Alois Alzheimer with dementia had psychotic symptoms 1 The symptoms in PAD are: 2,3 hallucinations delusions misidentifications Prevalence among AD patients is reported as 30 50% 2 Psychosis is commonly associated with agitation and aggression in demented patients 4 1. Alzheimer A. Allgemeine Zeitschrift für Psychiatrie und Psychisch Gerichtliche Medicin 1907; 64: Jeste DV, Finkel SI. Am J Geriatr Psychiatry 2000; 8: Sultzer DL. Dement Geriatr Cogn Disord 2004; 17: Reisberg B et al. J Clin Psychiatry 1987; 48: 9 15.

29 PAD: Distinct and definable Compared with patients with AD, those with PAD had 4 5-fold greater levels of abnormal tau protein in the entorhinal and temporal cortices 1 PAD correlates with frontal hypoperfusion on SPECT 3 and frontal hypometabolism with fpet 4 Predictive of more rapid disease progression 2,5,6 The FDA has endorsed PAD as a distinct and definable diagnosis 7 Current antipsychotics increase the risk of cerebrovascular events in AD patients New antipsychotics with improved efficacy and safety are needed fpet = functional positron emission tomography SPECT = single-photon emission computed tomography 1. Mukaetova-Ladinska EB et al. In: Treating Alzheimer s and other dementias. 2. Schneider LS, Dogerman KS. J Psychiatr Res 2004; 38: Mega MS et al. J Neurol Neurosurg Psychiatry 2000; 69: Sultzer DL et al. J Neuropsychiatry Clin Neurosci 1995; 7: Paulsen JS et al. Neurology 2000; 54: Stern Y et al. Neurology 1994; 44: Laughren T. Am J Geriatr Psychiatry 2001; 9: 340 5

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31 The mglu2/3 receptor agonist, LY379268, protects against Aß toxicity via TGF-ß1 release only in the presence of glial cells Pure cortical neurons Mixed cortical neurons only in the

32 LY M induces the release of the active form of TGF-β1 in rat cortical astrocytes

33 LY lost its neuroprotective activity in neurons grown with astrocytes lacking mglu3 receptors Caraci et al Mol Pharmacology

34 Potential pharmacological approaches to rescue neurotrophin signaling in AD Caraci & Drago Eur J Pharmacology 2010

35 Stress and dysfunction of the hypothalamic pituitary adrenal axis Chronic inflammation in depression and Alzheimer's disease Impairment of neurotrophin signalling in depression and AD: the role of BDNF and TGF-β1

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37 From depression to Alzheimer's disease: neurobiological links and hypothetical pathophysiological mechanisms MCI MCI Caraci et al. Eur J Pharmacology 2010

38 TGF-b1 is reduced in major depression Th1, Th2, and Th3 cytokine alterations in major depression Aye-Mu Myint et al Journal of Affective Disorders 88 (2005)

39 Deficit of TGF-β1 signaling is associated with severe depressive symptoms in AD

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41 TGF-b1 and depressive disorders Depression and AD are characterized by increased levels of pro-inflammatory cytokines IL-1b, IFN-, IL-6 TNF- Plasma TGF-ß1 levels are reduced in major depressed patients, and second-generation antidepressants, such as fluoxetine and sertraline increase circulating TGF-ß1 levels in major depressed patients Lee et al.2006

42 Potential pharmacological approaches to rescue neurotrophin signaling in depressed MCI patients at high risk to develop AD Caraci & Drago Eur J Pharmacology 2010