Natural non-trasgenic animal models for research in Alzheimer's disease

Abstract

The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Abeta precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Abeta) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Abeta cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Abeta-targeted drugs or new therapeutic strategies against this devastating disease.

Fig (1)

(1A-G). The canine model of Alzheimer’s disease. (A-C) Cortical Aβ pathology in the dog. (A) Brain section from a 13 years old Pekinese dog without Aβ deposits and (B-C) from a 20 years old individual of the same breed with extensive Aβ deposits. The three sections were stained in the same batch with 6E10 monoclonal antibody (Signet Lab. Dedham, USA). The level of B and C section is marked over the lateral view of the brain (inset). The earliest and more consistently affected areas in the dog were the prefrontal cortex, including the gyrus proreus (GP), the entorhinal cortex (ER) and the hippocampus (HP). However in severe cases as the one shown here (B and C), amyloid deposits spread throughout the cortex and can be found also in the caudate (arrowheads) and the claustrum (CL). (D-E) the anatomical distribution of the neurons expressing the low affinity nerve growth factor receptor (p75_NTR) in the basal forebrain of the dog. Section in D is at the level of the vertical and horizontal diagonal band (BDv and BDh, respectively); section in E is at the level of the dorsal and ventral subdivision of the intermediate part of nucleus basalis of Meynert (NBid and NBiv, respectively). Framed area in D and E are enlarged in the corresponding inset. (F) Double immunofluorescence staining showing that practically all magnocellular cholinergic neurons (red staining) in the basal forebrain co-express p75_NTR (green staining). (G) Co-expression of choline acetyl transferase (ChAT, red immunofluorescence) and NADPH-D (blue staining, bright field illumination) in most (~80%) of the basal magnocellular neurons in the anterior and intermediate parts of the dog (NBa and NBi respectively; yellow arrows). These images were presented at the 17th ECVIM-CA congress and 9th ESVCP congress. Budapest, September 2007. (Suárez M-L, Insua D, Corredoira A, Bernedo V, Santamarina G, and Pesini P. The basal forebrain cholinergic neurons in aged dogs with and without cortical amyloid pathology).