Alzheimer’s disease therapies: Selected advances and future perspectives

Peer review under responsibility of Alexandria University Faculty of Medicine.

Available online 18 October 2014

Abstract

Among the neurodegenerative diseases, Alzheimer’s disease (AD) represents one of the biggest challenges that the modern health care system has to deal with. The lack of data about the etiology and the complexity of the underlying pathogenesis constitute the biggest struggle facing the development of new therapeutical approaches. Within this paper we describe selected currently used approaches, point some challenges and give indications about the future perspectives in AD treatments. We hope this paper together with the selected references will contribute in putting spot light on the future of AD therapies and give guidelines for both professionals and researches working on that area of the brain diseases.

KEYWORDS:

• Alzheimer’s disease
• Therapies
• Perspectives

1 Introduction

One of the major challenges facing the modern health care system is the neurodegenerative diseases such as Alzheimer’s disease (AD)¹ that represents the most prevalent dementia.¹ AD represents a neurodegenerative disorder characterized by loss of neurons, cognition² and a progressive loss of brain functions.³ This disorder affects a large number of the human population, for instance in USA alone more than 5 million people suffer from AD.⁴ AD has heavy medical, economic and social consequences due not only to AD itself but also due to the related problems such as dementia, both dependency and disability among older people⁵ and vascular impairment.⁶

Although the AD-related neurodegenerative process remains unclear,⁷ description of some pathogenic processes has been reported. AD is associated with the aggregation of abnormal proteins² including amyloid beta (Aβ)protein^5,8 that aggregate into senile plaques⁹ in the brains of AD patients⁸ and the pathologically modified tau⁹ which are hyperphosphorylated⁵ and that aggregate into neurofibrillary tangles⁹ in the brain. Both neurons’ death and amyloid protein fibril accumulation lead to AD¹⁰ and the accumulation of Aβ in the brain leads to a chain of pathogenic processes n brains of AD patients.¹¹

Furthermore, other phenomena have been reported as parts of the AD pathological process including altered synaptic function,¹² Cerebral amyloid angiopathy¹³ and functional and morphological impairment of cerebral circulation.⁶ Importantly, neuroinflammation is also a key element within AD pathogenesis.¹⁴ Theses diverse elements reflect the different targets we can consider for AD therapeutic approaches.

2 Selected therapeutic advances

At present, current drug treatments of AD, such as cholinesterase inhibitors or NMDA antagonists,¹ mainly help to manage symptoms⁵ hereby obviating the need for new approaches to deal with AD underlying mechanisms. Indeed, some current therapeutic approaches include reversible cholinesterase inhibitor like rivastigmine.²

Epidemiological studies have important contributions to presenting new bases for future. For instance, risks of developing Alzheimer’s disease can be decreased by smoking tobacco and it was suggested that nicotine inhibits neuronal apoptosis which prevents the Aβ25–35-induced neurotoxicity¹⁵ pointing a starting point to new therapeutic approaches.

Natural products described by pharmacognosy constitute important resources for AD treatment especially after modern sciences have built bridges between Traditional Chinese Medicines and modern pharmacology.¹⁶ For instance, Malay traditional practitioners claimed that Aquilaria subintegra leaves can treat AD patients, supposedly via Acetyl choline inhibition¹⁷ and the amyloid formation could be inhibited by Silymarin which is a standardized extract of milk thistle.¹⁸ In addition, since inflammation is an element within AD pathogenesis¹⁴, extracts or compounds from plants with anti-Inflammatory properties such as Nigella glandulifera Freyn et Sint¹⁹ could provide a complementary therapy.

Importantly, different findings and ways for research deserve more attention. Molecules that inhibit Amyloid-β such as pinocembrin,¹¹ emerging therapeutic targets for the treatment of AD including Glucagon-like peptide-1¹⁴ represent good examples. Moreover, both the development of animal models of AD²⁰ and the description of molecules implicated in diverse pathogenesis such as cyclic peptides¹⁰ and the Aβ-targeted immunotherapy⁵ and cysteinyl leukotriene receptor 1 antagonism²¹ sphingosine 1-phosphate receptor²² 5-HT4 receptor-induced α-secretase activation²³ bring more hope toward identifying new targets.

3 Perspectives and challenges

The new methods including ultrasound⁶ and positron emission tomography²⁴ help for the early AD diagnosis. Furthermore, they allow us to follow the disease evolution during treatment and potentially identify new therapeutic targets. Indeed, AD development may be related to metabolic disorders like type-2 diabetes mellitus, insulin resistance, metabolic syndrome and obesity.²⁵ Moreover, Epidemiological data^15,25 diverse traditional medicines,¹⁷ animal studies²⁵ and the recent investigations about AD cellular and molecular aspects⁵ also provide strong starting points to develop new therapeutic approaches for AD.

Diverse approaches are under investigation and some have already shown promising results in AD patients. The immunotherapies that increase Aβ accumulation in preclinical models⁵ and metabolic-based therapies²⁵ represent good examples. We should extend our fields of thinking beyond antiamyloid therapy for AD.²⁶ Indeed, Tau-related immunotherapy is expected to see further development toward clinical trials⁵ as emerging therapeutic strategies for both tauopathies and AD.¹ Another example for AD treatment is the metal chelation; as metal binding with Aβ has been described.⁸ Further approaches to prevent spine degeneration in AD¹² seem urgent. At the same time research about AD must take into consideration the parameters that could influence the AD risks, pathogenesis⁵ or prognosis including Patient’s gender.⁴

However, AD researches still need to overcome different struggles including the regulations and the legal aspects²⁷ and the fact that different therapeutic theories require in vivo and biodistribution studies² before we see a speed up in the progress of AD researches.

Conflict of interest

None.

Acknowledgment

Abdelaziz Ghanemi is the recipient of a 2013 CAS-TWAS President’s Postgraduate Fellowship.

Notes

Peer review under responsibility of Alexandria University Faculty of Medicine.

Available online 18 October 2014