Animal models in the drug discovery pipeline for Alzheimer's disease

Abstract

With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes -which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2011.164.issue-4 Abbreviations Ab, amyloid-b; AD, Alzheimer's disease; APP, amyloid precursor protein; BACE1, b-site APP-cleaving enzyme 1; BPSD, behavioural and psychological signs and symptoms of dementia; EGFP, enhanced green fluorescent protein; GSK-3b, glycogen synthase kinase 3b; NFT, neurofibrillary tangle; PSEN, presenilin; SAM, senescence-accelerated mouse; SAMP, SAM-prone; TILLING, targeted induced local lesions in genomes; ZFN, zinc finger nuclease IntroductionAs the prototype of cortical dementias, Alzheimer's disease (AD) presents with prominent cognitive deficits. Initially, patients display limited forgetfulness with disruption of memory imprinting, which evolves to short-term memory disruption and, eventually, to long-term memory deficits. At more advanced stages, patients show executive dysfunctioning leading to advanced helplessness. Besides cognitive deterioration, patients display behavioural and psychological signs and symptoms of dementia (BPSD). BPSD is an umbrella term that embraces a heterogeneous group of noncognitive symptoms and behaviours, including paranoid and delusional ideation, hallucinations, activity disturbances, BJPBritish Journal of Pharmacology...

Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer's disease

“…Ab can impair synaptic function, typified by its ability to affect synaptic plasticity (reviewed in Venkitaramani et al, 2007;Selkoe, 2008), and trigger events leading to a loss of viability of synapses (Mattson et al, 1998;Shankar et al, 2007;Canas et al, 2009). Accordingly, the exposure to Ab is correlated (Lue et al, 1999;Näslund et al, 2000;Fagan et al, 2007) and leads to memory impairment (reviewed in Selkoe, 2008) and the intracerebroventricular administration of Ab has been proposed as a model of AD (reviewed in Lawlor and Young, 2010;Van Dam and De Deyn, 2011). This has allowed us to show that the pharmacological or genetic modification of presynaptic neuromodulation systems able to control synaptic function and viability, such as adenosine A 2A receptors, can prevent memory deterioration (Canas et al, 2009).…”

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

“…The neuropathological hallmarks of AD are extracellular senile plaques containing aggregates of the β-amyloid peptide (Aβ), and intraneuronal neurofibrillary tangles (NFTs) [2] [3] [4] that consist mainly of intracellular and abnormally phosphorylated tau protein [3] [5]. These pathologic features are accompanied by decreased synaptic density, which eventually leads to widespread neurodegeneration, loss of synapses and failure of neurotransmitter pathways, particularly those of the basal forebrain cholinergic system, especially in the hippocampus and cortex [3] [6]. Tau phosphorylation (ptau) is regulated by numerous Ser/Thr and phosphatases, including glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A); both are considered to be the major kinase and phosphatase in vivo [7] [8] [9].…”

Animal models of neurodegenerative diseases

“…11,12 As Ab is closely involved in AD pathogenesis, AD rodent models were generated by intracerebral infusion of Ab peptides. 13,14 Importantly, direct intracerebral injection of Ab peptides causes learning and memory deficits, as well as neuropathological changes that resemble human AD, including inflammation, microglial activation, and limited cell loss. The infusion model allows researchers to administer defined amounts of a specific Ab species of known sequence and length, rather than waiting several months (i.e., aging process) for the development of pathological changes in transgenic animals.…”