Barriers to developing a valid rodent model of Alzheimer's disease: from behavioral analysis to etiological mechanisms

Abstract

Sporadic Alzheimer's disease (AD) is the most prevalent form of age-related dementia. As such, great effort has been put forth to investigate the etiology, progression, and underlying mechanisms of the disease. Countless studies have been conducted, however, the details of this disease remain largely unknown. Rodent models provide opportunities to investigate certain aspects of AD that cannot be studied in humans. These animal models vary from study to study and have provided some insight, but no real advancements in the prevention or treatment of the disease. In this Hypothesis and Theory paper, we discuss what we perceive as barriers to impactful discovery in rodent AD research and we offer potential solutions for moving forward. Although no single model of AD is capable of providing the solution to the growing epidemic of the disease, we encourage a comprehensive approach that acknowledges the complex etiology of AD with the goal of enhancing the bidirectional translatability from bench to bedside and vice versa.

Looking beyond the standard version of the Morris water task in the assessment of mouse models of cognitive deficits

“…This AD model utilizes a novel knock-in approach to elevate amyloid beta, which differs from the widely used transgenic models that overexpress amyloid beta and all other amyloid precursor protein fragments (Gidyk et al, 2015;Masuda et al, 2016 ;Saito et al, 2014). The overexpression of all amyloid precursor proteins creates an artificial phenotype that is not representative of human AD pathology (Gidyk et al, 2015;Masuda et al, 2016;Saito et al, 2014). AppNL-G-F/NL-G-F mice develop amyloid plaques at 6 months of age and have behavioral deficits in flexibility, attention, and spatial learning (Masuda et al, 2016;Saito et al, 2014).…”

“…For these reasons, we have used this protocol to assess learning and memory in various experimental models, including alternative rat models of sporadic Alzheimer's disease (AD; for review see, Gidyk et al, 2015). Control rats are able to learn and retain the new location acquired during the massed training session, whereas rats given AD risk factors such as stroke, cholinergic depletion, or circadian rhythm disruption are typically not able to (Craig, Hong, Kopp, & McDonald, 2008a, 2008b, 2009a, 2009bMcDonald et al, 2005;McDonald, Craig, & Hong, 2008).…”

Boosting weakened synapses to treat Alzheimer’s disease

“…Accordingly, no good animal models of SAD currently exist, although we have developed a conceptual framework and examples of what these kinds of models might look like. Our basic idea is that the etiology of SAD is complex and heterogeneous, manifesting itself when the presence of various combinations of co-factors coexist (Craig, Hong, & McDonald, 2011;Gidyk et al, 2015). Proof of principle for this etiological theory comes from experiments showing that different combinations of co-factors linked to dementia produce HPC dysfunction and learning and memory impairments in rodents.…”

“…Treatments are largely ineffective for AD, and one explanation is that once the disease is recognized pathology is irreversible. Thus, recognizing and characterizing early AD is of paramount importance (Gidyk, Deibel, Hong, & McDonald, 2015).…”

Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation

“…The use of animal models in drug discovery has historically been integral to the development of novel therapies. Unfortunately, in many disease areas, the translatability of animal data into the clinical arena has been and continues to be challenging, with notable disconnects between the apparent effectiveness of various pharmacological agents across species, including humans (McGonigle and Ruggeri, 2014;de Caestecker et al, 2015;Gidyk et al, 2015;McNamee et al, 2015). This is particularly true in heterogeneous inflammatory diseases with complex multifaceted pathophysiology such as severe asthma or chronic obstructive pulmonary disease (COPD) (Grainge et al, 2016;Han et al, 2016;Powell, 2016;Vanfleteren et al, 2016).…”