Vol. 10, No. 3 2013 Drug Discovery Today: Technologies Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY TODAY TECHNOLOGIES Translational pharmacology Animal models of Alzheimer’s disease and drug development 1, 2 2 Bart Laurijssens *, Fabienne Aujard , Anisur Rahman 1 BEL Pharm Consulting, Moulin d’Ozil, 07140 Chambonas, France 2 CNRS UMR 7179, MNHN, 1 Av du Petit Chaˆteau, 91800 Brunoy, France Animal disease models are considered important in the Section editor: development of drugs for Alzheimer’s disease. This Oscar Della Pasqua – Leiden/Amsterdam Center for Drug brief review will discuss possible reasons why their Research, Leiden, The Netherlands. success in identifying efficacious treatments has been limited, and will provide some thoughts on the role of loss in brain regions involved in learning and memory pro- animal experimentation in drug development. Specifi- cesses (http://www.alz.org/) [1]. cally, none of the current models of Alzheimer’s dis- The interest in finding a cure or prevention for AD is ease have either construct or predictive validity, and no understandably great. Proper animal models of human AD are considered desirable if not essential in this process and model probably ever will. Clearly, specific animal much research effort has been put into that effect. As no experiments contribute to our understanding of the perfect model exists, the question becomes whether ‘the best disease and generate hypotheses. Ultimately, however, models available’ are good enough. What exactly can be the hypothesis can only be tested in human patients inferred from the results and what not? Or, differently put, how do they contribute to our understanding and decision- and only with the proper tools. These tools are a making. pharmacologically active intervention (in humans) The objective, therefore, of this brief review is to discuss the and a clinical trial suited to evaluate the mechanism potential role of the current animal disease models for AD in of action. Integration of knowledge in quantitative drug development. Specifically, the aim is to discuss why the (sub) models is considered important if not essential animal models of AD should have such a limited success in predicting successful treatments in the clinic (or rather, in this process. clinical trials), and to provide some thoughts on how to use animal experiments in drug development. Introduction Alzheimer’s disease (AD) is a neurodegenerative disease Animal models of Alzheimer’s disease affecting an estimated 5.4 million people globally, mainly The aetiology of AD is unknown, but there is still a general the elderly. There is currently no cure for AD, but some consensus in favour of the ‘amyloid hypothesis’ [1,2], even if symptomatic treatments are available. The disease is charac- it has been questioned [3]. A wide range of animal models terized by its hallmark histopathological findings of extra- have been developed to mimic the human context of the cellular b-amyloid (Ab) plaques and intracellular disease for the purpose of developing therapeutics or disease neurofibrillary tangles of tau and by neuronal and synaptic modifying agents. In fact, in most of the animal models the *Corresponding author.: B. Laurijssens ([email protected]) first goal is to simulate the neuropathological findings of AD 1740-6749/$ ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddtec.2012.04.001 e319 Drug Discovery Today: Technologies | Translational pharmacology Vol. 10, No. 3 2013 followed by the correlation of cognitive function without animal models reviewed in this section either show major knowing whether the neuropathological agents have similar AD-related neuropathology or are in close phylogenetic biological consequences in humans and in animal models. It proximity to humans. In recent years dogs have been con- is beyond the scope of this review to discuss all the different sidered as a useful animal model for AD due to the close models. Here we will briefly summarize some potential ani- proximity of canine and human brain aging. Dogs develop mal models and their translation towards the clinical settings extensive Ab and diffuse plaque deposition and the extent of (Table 1). Animal models used in AD can be broadly divided Ab deposition correlates with the decline of some measures of into three categories: Natural models, Genetic models and cognitive function in the absence of neurofibrillary tangles Interventional models. (NFTs). Moreover, the amino acid sequence of Ab is fully conserved between dogs and humans [5]. Because of sponta- Natural models neous age-related Ab deposition and relative ease of cognitive Several animals including polar bears, dogs, cats, goats and function assessment, aged dogs were used to evaluate inter- sheep and some non-human primates spontaneously develop ventions with the aim of reduction of Ab load and subsequent some AD-related neuropathological features [4]. The few cognitive improvement (Table 1). Table 1. Some animal models of AD and clinical trials Model Treatment active in model Clinical trial Natural models Dog Active immunization with Ab1-42 [49] Trial stopped due to CNS side effects [50] Antioxidant [49] No effects [51] Rhesus monkey Acetylcholinesterase inhibitor, Donepezil [14] Approved for AD Nicotinic receptor agonist ABT-418 [14] Discontinued for side effects Glutamate receptor blocker Memantine [14] Approved for AD Mouse lemur, Octodon, No pharmacological trial has been reported yet. Chimpanzees, Orang-utans, Polar bear, Cat, Sheep, Goat, Wolverine a Genetic models PDAPP mice Active immunization with aggregated Ab1–42 [52] Trial stopped due to CNS side effects [50] Passive immunization with IgG [53] Vasogenic oedema and microhaemorrhage in some patients, no significant cognitive benefit, Phase-III trials underway [53] APP mice b-Secretase inhibitor [54] Reduce plasma Ab significantly, Under phase-III clinical trial [62] Tg2576 mice g-Secretase inhibitors [55] Trial halted because the drug failed to stop disease progression, associated with worsening cognitive function and increased risk of skin cancer [63] g-Secretase modulators [56] No benefit, trial discontinued [62] Acetylcholinesterase inhibitor [57] Approved for AD Cognitive decline cannot be prevented, cognitive benefits with treatment associated adverse effects reported [64] PSAPP mice Non-steroidal anti-inflammatory drugs [58] Negative results [65] Tg-tau mice Simvastatin [59] No cognitive benefit [66] À/À Ttpa APPsw mice a-tocopherol [60] No efficacy [67] Fruit-fly Doxycycline [61] Together with Rifampin. Some positive effect on cognitive performance [68] Interventional models Rat Intrahippocampal amyloid infusion model Curcumin [69] In Phase-II [4] Intracerebroventricular Ab infusion model GSK3 inhibitor [70] Marginal benefits, larger trial ongoing [71] a PDAPP mice: Mutation of human APP with valine at residue 717 substituted by phenylalanine under the control of human platelet derived growth factor promoter. APP mice: Mutation of three isoforms [695, 751 and 770] of human APP under the control of various promoters. Tg2576 mice: Swedish double mutation [K670N/M671L] on the 695 human APP under the control of hamster prion protein promoter. PSAPP mice: Swedish double mutation [K670N/M671L] plus Presenilin 1 exon 9 deleted. Tg-tau mice: Human À/À normal shortest 3R tau isoform inserted into the mouse genome under the promoter. Ttpa APPsw mice: Tg2576 mice crossed with a-tocopherol transfer protein knockout mice [31,60]. e320 www.drugdiscoverytoday.com Vol. 10, No. 3 2013 Drug Discovery Today: Technologies | Translational pharmacology Among the non-human primate models, mouse lemurs Another interesting finding is the presence of extensive astro- seem to be a potential animal model that exhibit amyloid gliosis in the aged octodon brain, which is a characteristic plaque, NFTs and some other AD related neuropathology [6]. feature of human AD brain. It has been hypothesized that This small prosimian primate lives 8–10 years in captivity and high homology (97.5%) of octodon Ab and human Ab might shows age-related changes similar to those of aging humans be an important factor in the appearance of AD markers in [6]. About 20% of mouse lemurs aged five years or older show this rodent. Breeding difficulty and comparatively longer life- significant brain atrophy [7], extensive accumulation of amy- span are limitations of this rodent model [16,17]. loid plaques, neurodegeneration [8] and/or loss of cholinergic neurons [9]. The genes responsible for the formation of senile Genetic models plaques are highly similar between mouse lemurs and Transgenic technology provides unique opportunity to repro- humans [8]. The presence of amyloid deposition has been duce the cause of familial AD by transfecting a mutant human recently linked to cerebral atrophy in aged individuals, giving amyloid precursor protein (APP). Mice have extensively been new insight into the understanding of pathological aging in used as transgenic models and facilitated our understanding of this non-human primate species [10]. Moreover, a compar- the molecular mechanisms associated with Ab-production, able decline in declarative memory and executive function deposition and clearance and the effects of Ab on neuronal has been reported in both aged human and aged mouse lemur network and synapses that play important role in cognitive whereas procedural memory appears to be conserved in both function. The