Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

Abstract

A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer’s disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.

Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice

“…Preclinical models are a first step in understanding mechanisms underlying central nervous system disorders such as AD and offer researchers the potential to discover and test new approaches and screen novel therapeutics with the goal of successful translation into the clinic [ 42 , 43 ]. However, mouse AD models develop AD pathology to varying degrees with age, which often makes it challenging to obtain relevant preclinical findings on safety and efficacy [ 6 ].…”

Neuropathogenesis-on-chips for neurodegenerative diseases

“…Specifically, preclinical studies conducted on familial genetically engineered mouse models have limitations as they do not fully replicate all the features of NDs, especially sporadic cases. These models exhibit varied clinical and pathological phenotypes that restrict their effectiveness in translation to human physiology 558 . Moreover, long-term preservation of animals with age-related characteristics can be costly and time-consuming 559 .…”

Insight into the emerging and common experimental in-vivo models of Alzheimer’s disease

“… Animal model Major pathology Merits Demerits Method of administration /Dose References 1. Streptozotocin Neuroinflammation Oxidative stress Biochemical modulations Induces sporadic AD that is highly prevalent Long term development of amyloid and tau pathologies No effect on contextual fear memory, High mortality ICV/ 3 mg/kg [ 17 , 28 , 130 , 131 ] 2. Scopolamine Cholinergic dysfunction Different parameters can be evaluated therefore aids in developing multitarget therapy No Involvement of any surgical procedure Do not completely mimic AD pathologies Mainly used for preventive AD treatments ICV/ 2 mg/kg [ 28 , 32 , 36 , 132 , 133 ] 3.…”

“… Streptozotocin Neuroinflammation Oxidative stress Biochemical modulations Induces sporadic AD that is highly prevalent Long term development of amyloid and tau pathologies No effect on contextual fear memory, High mortality ICV/ 3 mg/kg [ 17 , 28 , 130 , 131 ] 2. Scopolamine Cholinergic dysfunction Different parameters can be evaluated therefore aids in developing multitarget therapy No Involvement of any surgical procedure Do not completely mimic AD pathologies Mainly used for preventive AD treatments ICV/ 2 mg/kg [ 28 , 32 , 36 , 132 , 133 ] 3. Colchicine Tau hyperphosphorylation Mimics sporadic AD pathologies Excitotoxicity can also be explored High mortality Adverse effects ICV/15 μg/5 μl Orally/0.3 mg/kg [ 28 , 42 , 61 ] 4.…”