ROLE OF NPY IN AD & PD

Role of Neuropeptide Y in Neurodegenerative Diseases

National Institute of Pharmaceutical Education and ResearchRaebareli

ByParth UpadhyayID No. 378/15

M.S. (Pharm.) Pharmacology & ToxicologySemester II

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Contents…IntroductionDistribution and localization of Neuropeptide Y

(NPY)The NPY receptorsNPY in neurodegerative diseases

NPY in Alzheimer’s Disease (AD)NPY in Parkinson’s Disease (PD)

Conclusion

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IntroductionNPY is a 36-amino acid peptide belonging to

a family of peptides that includes pancreatic polypeptide (PP) and peptide YY (PYY).

Isolated by Tatemoto and colleagues in 1982 (Tatemoto et al., 1982).

Fig.1 Structure of NPY(Source: Robertson, 2011)

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Synthesis of NPYPre-pro NPY ( 97 a.a.)

Pro- NPY (69 a.a.)Prohormone covertases

NPY1-39 + C-flanking peptide of NPY

Carboxypeptidase and Monooxygenase

NPY1-36

Transfers to rough E.R.

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Well established actions of NPYRegulation of food intake

Alleviation of anxiety

Stress and neuromodulatory effects

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Distribution and LocalizationAbundantly present in hypothalamus, amygdala.

Moderate levels are found in basal ganglia and thalamus.

Also high levels are found in cortex.

Co-releases with monoamines and glutamate.

This may suggest its important functions in brain.

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The NPY ReceptorsSix types : Y1, Y2, Y3, Y4, Y5 and Y6.

Y1, Y2 and Y5 are activated by NPY and PYY, while Y4 preferentially bind PP.

Y1 receptors: Functions in food intake, anxiety, pain, ethanol intake. Expressed in amygdala, thalamus and hypothalamus.

Y2 receptors: Functions in feeding and body weight, angiogenesis, bone formation, epilepsy, learning and memory and anxiety. Found in cortex, hippocampus, amygdala, thalamus, hypothalamus and striatum.

Y3 receptors: Not cloned yet.

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The NPY ReceptorsY4 receptors: Involved in food intake and found in

hypothalamus.Y5 receptors: Functions in food intake, circadian

rhythms, reproductive endocrine functions and found majorly in cortex, hippocampus and amygdala.

Y6 receptors: Expressed in mouse; absent in rat. Expressed in hypothalamus and have a role in bone formation. No role in food intake.

Co-localization of Y1 and Y5 receptors have also been found in cerebral cortex, caudate putamen, basolateral amygdala.

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NPY in neurodegenerative diseaseAetiology is not well known but several genetic and

environmental factors and age are possible cause.

Also due to excitotoxicity; NPY has capacity to buffer this excitotoxicity and subsequent neuronal damage.

Very few studies have explored the effects of NPY in neurodegenerative disease.

AD and PD are most prevalent neurodegenerative diseases.

NPY in Alzheimer’s

Disease

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NPY changes in AD brainAD is a progressive neurodegenerative disease

characterized by amyloid plaques consisting of β-amyloid protein (Aβ) and Tau protein tangle.

Decreased neuronal mass and NPY in AD (Beal et al., 1986).

Decreased NPY-like immunoreactivity (NPY-ir) in temporal lobe, frontal lobe, and occipital cortex (Beal et al., 1986; Davies et al., 1990).

Plasma and CSF NPY levels are decreased (Koide et al., 1995; Nilsson et al., 2001).

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NPY changes in AD

All these changes in NPY may serve NPY as a biomarker in AD (Edvinsson et al., 1993).

Decrease in NPY level firstly in cortex and

hippocampus (Ramos et al., 2006; Albuquerque et al., 2015)

Increased NPY level (Diez et al., 2000; 2003)

Counter response to nerve injury

Fig.2 Counter response of NPY in AD

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NPY in ADStudies by Croce and his team

The cell loss due to the toxic effect of beta-Amyloid protein (Aβ) is prevented by NPY. Nerve growth factors and Brain derived neurotrophic factors (BDNF) are also restored.

On rat cortical slices, same results are achieved.

To explore its mechanism, further study revealed increased mRNA expression of BDNF.

Anti-oxidan

t activit

y

↑ mRNA expressio

n of BDNF

Neuroprotection and

Neuroregeneration

Fig. 3 Effects of NPY in AD

NPY

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NPY in AD Infusion of NPY C-terminal fragments in amyloid

precursor protein (APP) in transgenic mice ameliorates the neurodegenerative pathology (Rose et al., 2009).

Same results has been obtained in human neuronal cultures (Rose et al., 2009).

Oxidative stress due to Aβ is abolished by NPY. This preventive action was abolished by the administration of selective Y2 receptor antagonist, BIIE0246 Role of Y2 receptors is explored (dos Santos et al., 2013).

These all studies provided neuroprotective and neuroregenerative actions of NPY in AD and involvement of Y2 receptors.

NPY in Parkinson’s

Disease

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NPY in PD Degeneration in dopaminergic nirostriatal

neurons, characterized by Lewy bodies.

NPY are in close juxtaposition to dopaminergic neurons in striatum (Adewale et al., 2005).

NPY regulates dopamine and other monoamines release inhibitory action (Benarroch, 2009).

In 6-OHDA & MPTP lesioned rats has showed an increase in NPY-like immunoreactivity (NPY-ir) in nigrostriatal track (Kerkerian et al., 1986; Obuchowicz et al., 2003).

Intracerebroventricular administration of NPY increases dopamine release in rat striatum (Kerkerian-Le Goff et al., 1992).

NPY Dopamine

↓ Dopamine

↑ Dopamine

Physiology

Pathology

Fig. 4 Effect of NPY on dopamine

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NPY in PDHuman studies

In post-mortem parkinsonian brain, number of NPY mRNA-expressing cells were increased in caudate nucleus and putamen (Cannizzaro et al., 2003).

Whereas in the earlier study, NPY in the CSF of PD patients was lower compared to normal individual (Martignoni et al., 1992), suggest the increased turnover of NPY in PD patients.

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NPY in PD: Involvement of NPY receptorsY2 receptor stimulates

dopamine release while the release is attenuated by Y1 and Y5 receptors (Adewale etal., 2005, 2007).

Y2 receptor agonist has also showed a neuroprotective effect of NPY in striatal neurons, while in transgenic mice lacked Y2 receptors has not showed any neuroprotective effect of NPY(Decressac et al., 2012).

↑ Dopamin

eand

Neuro-protectio

n

Y1 Attenuati

on

Y2 Stimulati

onY5

Attenuation

Fig. 5 Role of NPY receptors in PD

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ConclusionNPY and its receptors are abundantly found

throughout the brain.

NPY has showed promising neuroprotective and neuroregenerative actions in AD and PD.

Y2 receptor has showed neuroprotective actions in AD.

Y1, Y2 and Y5 receptors may also serve as a targets in PD.

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Reference Tatemoto, K., Carlquist, M., Mutt, V., 1982. Neuropeptide Y-A novel brain peptide with structural similarities to peptide YY

and pancreatic peptide. Nature 296, 659-660. Beal M.F., Mazurek M.F., Chattha G.K., Svendsen C.N., Bird E.D., Martin J.B., 1986. Neuropeptide Y immunoreactivity is

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Croce N, Ciotti MT, Gelfo F, Cortelli S, Federici G, Caltagirone C, Bernardini S, Angelucci F., 2012. Neuropeptide Y protects rat cortical neurons against β-amyloid toxicity and re-establishes synthesis and release of nerve growth factor. ACS Chem Neurosci. 3, 312-8.

Croce N, Dinallo V, Ricci V, Federici G, Caltagirone C, Bernardini S, Angelucci F., 2011. Neuroprotective effect of neuropeptide Y against β-amyloid 25-35 toxicity in SH-SY5Y neuroblastoma cells is associated with increased neurotrophin production. Neurodegener Dis. 8, 300-9.

Croce N., Ciotti M.T., Gelfo F., Cortelli S., Federici G., Caltagirone C., Bernardini S., Angelucci F., 2012. Neuropeptide Y protects rat cortical neurons against β-amyloid toxicity and re-establishes synthesis and release of nerve growth factor. ACS Chem Neurosci. 3, 312-8.

Croce N., Gelfo F., Ciotti M.T., Federici G., Caltagirone C., Bernardini S., Angelucci F., 2013. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?. Mol Cell Biochem. 376, 189-95.

dos Santos VV, Santos DB, Lach G, Rodrigues AL, Farina M, De Lima TC, Prediger RD., 2013. Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ(1-40)) administration in mice. Behav Brain Res. 244, 107-15.

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