Transgenic mice expressing the human presenilin 1 gene demonstrate enhanced hippocampal reorganization following entorhinal cortex lesions

Abstract

We have examined the effects of the presence of the mutated human presenilin 1 gene (M146L; hps1∗) on lesion-induced sprouting in the hippocampus of the mouse (C57/CBA). The entorhinal cortex was unilaterally lesioned with ibotenic acid in adult, male mice. Four weeks later the subsequent axonal sprouting in the dentate gyrus was analysed, by measuring the density of the synaptophysin immunocytochemical staining in the termination area of the entorhinal cortex axons. The data demonstrate that mice expressing either the human presenilin 1 gene (hps1) or the hps1∗ gene display a significantly increased density of immunocytochemical staining for synaptophysin, indicative of axonal sprouting, compared to the control mice. No (or a very small) sprouting response is observed in mice expressing the normal mouse ps1 gene. Taken together, these data indicate that the presence of a human ps1 gene, normal or with an Alzheimer’s disease mutation, leads to enhanced plasticity in the mouse brain.

Introduction

Alzheimer’s disease (AD) is characterized by appearance of amyloid plaques, neurofibrillary tangles, and loss of neuronal elements [34]. Autosomal dominant early onset AD is caused by mutations of the amyloid precursor protein (APP) gene and the presenilin1 (ps1) and presenilin2 (ps2) genes. Each of these affect APP metabolism and amyloid beta (Aβ) protein production (e.g., [34]). The aberrant metabolism of APP may be causally related to the development of dementia by leading to the formation of neurofibrillary tangles, and loss of synapses and neurotransmitters in the medial temporal lobe memory areas and cortical associational regions 2, 34. Mutations in the ps1 gene have been shown to alter APP processing, resulting in an increase of the more amyloidogenic Aβ_1–42 vs. Aβ_1–40 (e.g., [1]), the 42-amino acid peptide form of Aβ, which is the major component of the amyloid plaques that are present in the brains of AD patients [45]. PS1 not only plays a role in APP processing, but it has also been shown to be involved in cortical development, i.e., PS1 has been shown to play a major role in the Notch signalling pathway (e.g. 15, 36, 51). Other recent studies have shown that PS1 could play a more direct role in brain plasticity, e.g., mice expressing a hps1 gene containing an AD mutation display increased hippocampal long-term potentiation compared to mice expressing the normal gene [33]. Transfected neuroblastoma cells expressing ps1 mutations demonstrate impaired neurite outgrowth compared to non-transfected cells [8], in contrast a recent study has demonstrated that PS1 mutations deregulate neurite growth, i.e., in differentiated neurons a PS1 mutation promotes a marked increase in total neurite length [33]. Further, increases in neuronal plasticity appear to contribute importantly to the development of the pathological hallmarks of AD (i.e., to the development of plaques and tangles [29]).

The phenomenon of plasticity, or more specifically, axonal reorganization is of interest because, quite often, following injury to the central nervous system (CNS), the response of the CNS is an elaboration of new synaptic contacts by afferent systems that terminate near the denervated site (e.g., [43]). One of the most studied systems in brain plasticity following injury has been the regrowth of entorhinal axons in the dentate gyrus of the rat following unilateral entorhinal cortex lesions. Many studies have demonstrated that, following entorhinal cortex ablations, the dentate gyrus of the hippocampus shows an early phase of degeneration of the lesioned axons and terminals, followed later by a sprouting response of non-lesioned axons (e.g., [43]). In addition, it should be noted that it has been suggested that the cortical area that is affected earliest in AD is the entorhinal cortex [2]. Based on these data we have hypothesized that mice expressing a mutant form of the human ps1 gene will show alterations in hippocampal sprouting following entorhinal cortex lesions.

The results of this study show that the process of cortical reorganization following entorhinal cortex lesions is not disturbed in these transgenic AD-model mice, the data indicate that the presence of a hps1 gene, normal or with an AD mutation, leads to enhanced axonal plasticity.