Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome

doi:10.1016/j.ejphar.2017.10.004

European Journal of Pharmacology

Volume 817, 15 December 2017, Pages 7-19

https://doi.org/10.1016/j.ejphar.2017.10.004 Get rights and content

Abstract

Individuals with Down syndrome are at increased risk of developing Alzheimer's disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimer's disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimer's disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease-modifying therapies for the benefit of Down syndrome individuals and for Alzheimer's sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best-validated pharmacological targets for the treatment of cognitive impairment and Alzheimer's disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population.

Introduction

Down syndrome is the most common chromosomal abnormality leading to intellectual disabilities (Gardiner et al., 2010). The excess gene dosage in Down syndrome is associated with characteristic facial and physical features, deficits in immune and endocrine systems, congenital heart defects and delayed growth (Roizen and Patterson, 2003) combined with deficits in learning and language that lead to a mild-to-moderate global cognitive impairment (Lott and Dierssen, 2010, Zigman et al., 2008). Given the advances in medical and social care of the past decades, the life expectancy of individuals with Down syndrome has greatly increased, such that many live well into their 60s and 70s. This means that pathological conditions associated for aging, as is the case for dementia, are also more present in this population.

Alzheimer's disease is the most common form of dementia that develops in individuals with Down syndrome, as in the general population (Zigman et al., 1996). Unfortunately, no disease-modifying drugs are yet available to treat dementia in Down syndrome. In that sense, biomarker discovery and the development of sensitive cognitive screening tools will be essential for earlier diagnosis and better therapeutic management.

In the present review we will describe the pathophysiology of Alzheimer's disease in Down syndrome examining the best validated pharmacological targets that are presently considered for clinical trials. In particular we examine the dysfunction of different genes and neurotransmitter-based systems, including the cholinergic deficit concomitant with the metabolic deregulation of the NGF metabolic pathway, a novel neurochemical pathway that has been validated as a potential pharmacological target for the treatment of Alzheimer's disease pathology in Down syndrome. We further examine the relevance of biological markers for an early diagnosis of Alzheimer's disease in Down syndrome and the recent clinical trials designed to assess the possible disease-modifying activity of new drugs under investigation.

Section snippets

Alzheimer's disease in Down syndrome: from clinical phenotypes to neurobiology

The amyloid cascade hypothesis posits that overproduction or impaired clearance of amyloid-β (Aβ) causes Alzheimer's disease as a result of the aggregation of monomeric Aβ species into higher-molecular-weight oligomers that result in neuronal loss (Selkoe and Hardy, 2016). Individuals with Down syndrome show an increased risk of developing Alzheimer's disease, as a consequence of trisomy 21 with the associated over-production of the amyloid precursor protein (APP) and of its amyloidogenic

Diagnosing Alzheimer's disease in Down syndrome: the role of biological markers

Although there are specific cognitive screening tests designed for individuals with Down syndrome, there are no formal guidelines for the diagnosis of dementia in this population, unlike in the elderly or in familial genetic cases (e.g. ICD-10 criteria). Further challenges to the diagnosis of dementia in Down syndrome are the atypical presentation of Alzheimer's symptoms (e.g. beginning mainly with changes in mood and behaviour rather than with memory problems), the difficulty in dissecting

Correcting the dysfunction of neurotransmitter systems

Different neurotransmitter-based systems are known to play a central role in cognitive decline in Down syndrome (Das et al., 2014). Neurodegeneration of basal forebrain cholinergic neurons (BFCNs) is a primary event in the pathogenesis of Alzheimer's disease in Down syndrome (Salehi et al., 2006), but recent studies on cognitive dysfunction emphasize the relevance of other neurotransmitter-based systems such as an imbalance between excitatory (i.e. glutamatergic) and the major inhibitory system

Overview and challenges for testing disease-modifying drugs in Down syndrome

Recent efforts have been directed to develop disease-modifying drugs to counteract the progression of Alzheimer's disease in Down syndrome (Hartley et al., 2015). The design of clinical trials in this population raises methodological challenges in studying cognitive functioning and assessing the neuroprotective effect of a potential disease-modifying drug. According to the European Medical Association and the Food and Drug Administration, a drug is considered to be disease modifying when it is

Conclusions and perspectives

Preclinical studies point at several strategies and novel targets to improve or protect cognitive function in Down syndrome. These include correcting neurotransmitter deficits, such as cholinergic, noradrenergic and serotonergic neurodegeneration, reducing GABA hyperactivity, targeting glutamate excitotoxicity as well as inhibiting DYRK1A activity and correcting NGF metabolic deregulation. The field of biomarker discovery in Down syndrome is another fertile territory of active investigation,

Acknowledgements

FC would like to acknowledge support from the Neuropsychopharmacology Research Program 2017 (RC-06-01) and from the Institute for Research on Mental Retardation and Brain Aging, Troina, Italy. MFI was the recipient of the Herbert H. Jasper Postdoctoral Research Fellowship in Neurosciences from the Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal (2016–2017), and was also supported by a Bourse de Recherche Postdoctorale from the Fonds de recherche du Québec -

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Full length articleSearching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome

Abstract

Introduction

Section snippets

Alzheimer's disease in Down syndrome: from clinical phenotypes to neurobiology

Diagnosing Alzheimer's disease in Down syndrome: the role of biological markers

Correcting the dysfunction of neurotransmitter systems

Overview and challenges for testing disease-modifying drugs in Down syndrome

Conclusions and perspectives

Acknowledgements

Pharmacol. Ther.

Neurobiol. Dis.

Exp. Neurol.

Neurosci. Lett.

Neurobiol. Dis.

Brain Res Brain Res Rev.

Early Hum. Dev.

Neurobiol. Learn Mem.

Cell

Adv. Pharmacol.

Progress. brain Res.

Biol. Psychiatry

Progress. neuro-Psychopharmacol. Biol. Psychiatry

Lancet

Lancet Neurol.

Progress. brain Res.

Cortex; a J. devoted the Study Nerv. Syst. Behav.

Neurosci. Lett.

Mol. Cell. Neurosci.

Neurobiol. Dis.

Neurochem. Int.

Mol. brain Res.

Neurobiol. Dis.

Biochim. Et. Biophys. Acta (BBA)-Mol. Basis Dis.

Mol. Brain Res.

Exp. Neurol.

Alzheimer'S. Dement.: J. Alzheimer'S. Assoc.

Alzheimer'S. Dement.: J. Alzheimer'S. Assoc.

Alzheimer'S. Dement.: J. Alzheimer'S. Assoc.

J. Biol. Chem.

Behav. brain Res.

Neurobiol. Aging

Behav. brain Res.

Neurochem. Int.

Trends Pharmacol. Sci.

Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype

J. Neurosci.

The quest for small molecules as amyloid inhibiting therapies for Alzheimer's disease

J. Alzheimer's dis.

Executive dysfunction and its association with personality and behaviour changes in the development of Alzheimer's disease in adults with Down syndrome and mild to moderate learning disabilities

Br. J. Clin. Psychol.

Is it possible to improve neurodevelopmental abnormalities in Down syndrome?

Rev. Neurosci.

Hippocampal myo-inositol and cognitive ability in adults with Down syndrome: an in vivo proton magnetic resonance spectroscopy study

Arch. General. Psychiatry

DYRK1A: a potential drug target for multiple Down syndrome neuropathologies

CNS Neurol. Disord. Drug Targets

The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand

J. Cereb. Blood Flow. Metab.

Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory

J. Cell Sci.

Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome

J. Neurosci.: Off. J. Soc. Neurosci.

Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

Transl. Psychiatry

Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies

Brain: a J. Neurol.

Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade

Proc. Natl. Acad. Sci.

Amyloid β-induced nerve growth factor dysmetabolism in Alzheimer disease

J. Neuropathol. Exp. Neurol.

The Anti-Inflammatory Role of Minocycline in Alzheimer´ s Disease

Curr. Alzheimer Res.

Depression and the onset of dementia in adults with mental retardation

Am. J. Ment. Retard.: AJMR

Full length article
Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome