These abnormal protein inclusions alter neuronal function and result in neuron death. Human AD neurons also contain intraneuronal inclusions of hyperphosphorylated tau protein, called neurofibrillary tangles (reviewed by ). Presenilin-1 (PS-1) and presenilin-2 (PS-2) function as a catalytic site for γ-secretase and mutations in PS-1 or PS-2 further increase the production of amyloidogenic A β. APP mutations alter the processing of the protein by shifting the nonamyloidogenic processing towards amyloidogenic processing which eventually leads to generation of highly fibrillogenic, toxic A β1-42 peptides. These peptides are cleavage products derived from the amyloid precursor protein (APP) through endoproteolytic cleavage operated by specific secretases, BACE-1 and γ-secretase. One of the pathological features of the disease is the abnormal accumulation of toxic A β peptides in the brain parenchyma.
APPswe/PS1dE9 Mice as a Model of ADĪD is a multifactorial disorder leading to progressive memory loss and eventually death. Studies utilizing APPswe/PS1dE9 mice as a model of AD are discussed below in the context of virus vector-mediated and cell-based experimental therapy in vivo. Therefore, these mice offer a valuable tool in studies of cell mediated A β clearance. Importantly, similar to some clinical AD cases, the behavioral deficits correlate with the soluble A β levels in the brain of this mouse line.
APPswe/PS1dE9 mice accumulate toxic A β in the brain parenchyma, and also around the blood vessels as cerebral amyloid angiopathy (CAA) upon aging, making them excellent models for AD’s amyloidosis. Similarly, although the brain is an evident target tissue of the cell-based therapy, cells administered peripherally may function also in peripheral sites. The main strategies adopted for viral vector-mediated gene delivery to the CNS include direct delivery into the brain parenchyma and peripheral delivery.
The targets of gene therapy for AD fall into four main categories: catabolism of amyloid precursor protein (APP) and removal of A β, neuroprotective genes, growth factors, and apolipoprotein E (ApoE) alleles. The central nervous system (CNS) is a unique site that poses challenges to the delivery of therapeutics as efficient delivery requires the crossing of the blood brain barrier (BBB). Since AD is a multifactorial disorder that progresses slowly, it is important to choose a gene transfer approach that allows lengthy expression of the therapeutic gene and/or a cell-based therapeutic strategy that results in sufficient and preferably long-term reduction in A β levels. On the other hand, the cell therapy-based applications in combating AD are based on the rationale of replacement of functionally lost neurons by transplantation of neuronal stem or progenitor cells, improvement in diminished neuronal function by creating an environment aiding at neuronal recovery, or clearing of toxic beta-amyloid (A β) plaques by phagocytic cells. This technology allows the delivery of DNA to target cells to achieve the expression of a protective or therapeutic protein and also in neurodegenerative diseases, including Alzheimer’s disease (AD). Recent advances in the field of gene transfer technology have allowed the delivery of DNA into target cells of the recipient based on the use of viral systems for gene therapy. Both gene therapy and cell based therapy may be feasible therapeutic approaches for human AD. Here we review the current utilization of APPswe/PS1dE9 mice in testing gene transfer and cell transplantation aimed at improving the protection of the neurons against A β toxicity and also reducing the brain levels of A β. As gene transfer technology allows the delivery of DNA into target cells to achieve the expression of a protective or therapeutic protein, and stem cell transplantation may create an environment supporting neuronal functions and clearing A β plaques, these therapeutic approaches alone or in combination represent potential therapeutic strategies that need to be tested in relevant animal models before testing in clinics. These mice show increase in parenchymal A β load with A β plaques starting from the age of four months, glial activation, and deficits in cognitive functions at the age of 6 months demonstrated by radial arm water maze and 12-13 months seen with Morris Water Maze test.
One of the most extensively used transgenic mouse model of Alzheimer’s disease (AD) is APPswe/PS1dE9 mice, which over express the Swedish mutation of APP together with PS1 deleted in exon 9.
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