Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

Abstract

To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach.

Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI‐MSI

“…microRNAs have received increasing attention in neurodegenerative diseases and growing evidence suggests that alterations in the microRNA levels are linked to synaptic dysfunction. [33][34][35] Therefore, AD and synapse-related microRNA expression levels can be measured at the neonatal AD mouse models to further test this hypothesis.…”

“…In the light of these preliminary findings, we report the hypothesis of “alterations in the synaptic function are an early and common neurobiological threat and can be positioned at the very beginning of the pathways that contribute to the pathogenesis of AD”. microRNAs have received increasing attention in neurodegenerative diseases and growing evidence suggests that alterations in the microRNA levels are linked to synaptic dysfunction 33–35 . Therefore, AD and synapse‐related microRNA expression levels can be measured at the neonatal AD mouse models to further test this hypothesis.…”

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

“…Many of these animal models recapitulate key aspects of the disease, but all have failed to fully encompass the entire spectrum of human AD pathology ( Claussnitzer et al . 2020 ; Qin et al . 2020 ).…”

Gene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice

“…An interesting period in this progression is the presymptomatic stage, which occurs between the earliest pathogenic event of AD and the appearance of behavioral symptoms such as cognitive deficits. This stage could serve to identify early molecular alterations and novel interventions to delay, detect or counteract AD pathophysiology (Maccarrone et al, 2018;Qin et al, 2020). Indeed, animal models have become a useful tool to characterize possible molecular changes prior to any behavioral alteration (Caselli and Reiman, 2012).…”