During the past decades, a variety of rodent models have been developed and proven to be valuable tools for deciphering the complexity of AD and contributed to the discovery and development of diagnostic and therapeutic innovations. However, the current AD animal models have their limitations and may, at least partly, contribute to the high failure rates of AD drug candidates in clinical trials. Apart from the obvious gap between mice and men, the translational gap also stems from differences in etiological factors, spatio-temporal onset of pathology, and brain physiology [6
Notwithstanding the above, the AD mouse models are of utmost importance for the exploration of novel therapeutic approaches. Given the particularities and limitations of the animal models, the single most important parameter for meaningful proof-of-concept studies is the selection of the most appropriate animal model which most faithfully recapitulates the key parameters of disease. In addition, preclinical proof-of-concept studies should ideally be performed in more than one model to capture as much disease pathology as possible and to discern animal and model specific artifacts. For instance, by analyzing two models with different APP mutations, compounds acting specific in the context of one particular mutation would be distinguished.
The APP-Ld mouse model for amyloid pathology represents a highly valuable model for drug testing, especially when targeting the amyloid cascade, but also for modulators of beginning Tau pathology. As summarized in this paper, the processing of human APP-Ld and production of Abeta in APP-Ld mice result in a plethora of pathological and behavioral effects modeling key disease parameters of AD.
Development of amyloyd plaque pathology in brain parenchyma and vasculature, and related inflammatory processes (astrocytosis, microgliosis) arise in an age-dependent way. Concomitant clearance of Abeta to CSF is affected as a presumed consequence of massive deposition of Abeta. Thus, the resultant decrease of Abeta CSF (in function of age) closely mimics the situation in AD patients and provides an efficacy biomarker in preclinical studies directed to evaluate Abeta-modulating drugs.
The novel data on the presence of insoluble pyroglutamate-modified Abeta3–42 in the brain of aged APP-Ld mice offer alternative therapeutic options. N-terminal truncated Abeta is highly abundant in AD brain and is believed to be an initiator of the Abeta aggregation cascade because of its exceptional physical properties. The conservation of the QC mediated posttranslational modification process provides unique opportunities to study the role of pyroglutamate-modified Abeta in AD and for testing novel QC inhibitors for therapeutic potential.
Early formed soluble aggregates of Abeta (as of 2 months) in brain of APP-Ld mice suggest that these Abeta misconformers are primary triggers of synaptic and neurotoxicity. The similarity with AD patients is striking, especially in light of recent findings demonstrating that soluble oligomers species were elevated in AD brain and appear to correlate with cognitive decline and neuropathological hallmarks [35
]. Although the exact nature of the toxic Abeta species remains elusive, more than 25 years after their discovery, this finding can have an important impact on drug development strategies aimed at Abeta pathobiology.
Abeta-mediated activation of GSK3β
-kinases and phosphorylation of endogenous mouse Tau in APP-Ld mouse brain reflect an intriguing and potentially very important connection between Abeta and Tau pathology [1
]. Thus, the APP-Ld transgenics also model disease relevant Tau pathology [40
] and would permit studies of Abeta effects on Tau pathology and assessing the therapeutic potential of Tau modulators.
Collectively, APP-Ld mice recapitulate the AD-related development and progression of Abeta pathobiology and its downstream effects on cognition and Tau most closely, however, without neurofibrillary tangles and massive neuronal loss. This positions the APP-Ld mouse model as a valuable tool for detecting and analyzing Abeta and Tau modulating AD drugs with the potential to fundamentally modify the course of the disease. By combining APP-Ld with mutant PS1, a further aggravated Abeta pathology is obtained providing practical advances for especially proof-of-concept studies of drug candidates. The APP-Ld*TAU-P301L double transgenics offer the advantage of a more complete pathology facilitating research and drug development focusing or addressing the interplay of Abeta and Tau in onset and progression of AD.