Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein

Abstract

Proteolytic processing of amyloid precursor protein (APP) through an endosomal/lysosomal pathway generates carboxy-terminal polypeptides that contain an intact beta-amyloid domain. Cleavage by as-yet unidentified proteases releases the beta-amyloid peptide in soluble form. In Alzheimer's disease, aggregated beta-amyloid is deposited in extracellular neuritic plaques. Although most of the molecular mechanisms involving beta-amyloid and APP in the aetiology of Alzheimer's disease are still unclear, changes in APP metabolism may be important in the pathogenesis of the disease. Here we show that transgenic mice expressing the amyloidogenic carboxy-terminal 104 amino acids of APP develop, with ageing, extracellular beta-amyloid immunoreactivity, increased gliosis and microglial reactivity, as well as cell loss in the CA1 region of the hippocampus. Adult transgenic mice demonstrate spatial-learning deficits in the Morris water maze and in maintenance of long-term potentiation (LTP). Our results indicate that alterations in the processing of APP may have considerable physiological effects on synaptic plasticity.

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…To date, nine research groups have independently created transgenic mouse lines expressing various CTF forms of the human APP in the brain. Five of these lines showed either neuronal atrophy Oster-Granite et al, 1996;Nalbantoglu et al, 1997;Sato et al, 1997) or impaired learning (Nalbantoglu et al, 1997;Berger-Sweeney et al, 1999;Lalonde et al, 2002a) at age 12 -28 months, whereas the other four lines including the recent reported one did not display any obvious neuronal loss or cognitive impairment (Shoji et al, 1990;Sandhu et al, 1991;Araki et al, 1994;Sberna et al, 1998;Li et al, 1999;Rutten et al, 2003). Thus, the developed transgenic mice expressing CTFs showed conflicting results that ranged from no phenotype to AD-like pathogenesis.…”

“…Adopting this strategy basically eliminated the possibility of phenotypic variations resulting from compound genetic backgrounds, as encountered in other CTF-or APP-expressing transgenic lines. In fact, previously created CTF-expressing transgenic lines have compound genetic backgrounds, such as the C57BL/6 -DBA/2 hybrids (Li et al, 1999;Rutten et al, 2003), the C57BL/6 -SJL hybrids (Kammesheidt et al, 1992;Fukuchi et al, 1996;Oster-Granite et al, 1996), or the C3H -C57BL/6 hybrids (Nalbantoglu et al, 1997;Sato et al, 1997). We speculate that these complicated genetic backgrounds and different topographic configuration of expressed CTFs with respect to the cellular membrane, and transgene expression levels, contribute to the diversity of published data on the role of CTFs in the aging brain.…”

“…Accordingly, the in vivo role of hCTF99 remains elusive. All CTFexpressing transgenic lines developed thus far were created from compound genetic backgrounds, such as the C57BL/6 -DBA/2 hybrids (Li et al, 1999;Rutten et al, 2003), the C57BL/6 -SJL hybrids (Kammesheidt et al, 1992;Fukuchi et al, 1996;OsterGranite et al, 1996), or the C3H -C57BL/6 hybrids (Nalbantoglu et al, 1997;Sato et al, 1997). It is not clear whether these complex genetic backgrounds contribute to the conflicting results on the in vivo role of hCTF99 or the difference in the design of transgenic cassettes including the choices of promoters and the specific sequences of the transgene itself is involved.…”

Age-related impairments of new memories reflect failures of learning, not retention

“…The majority of published data regarding cognitive aging describes impairments of animals' learning abilities (Gage and Dunnett 1984;Markowska et al 1994;Meliska et al 1997;Nalbantoglu et al 1997;Vogel et al 2002;Matzel et al 2008), although a smaller percentage of these studies also report animals' performances after long retention intervals. Of those studies that report retention deficits, in most of those studies the initial learning upon which the long-term memory was based was impaired relative to young animals (e.g., Barnes and McNaughton 1985;Kinney et al 2001a,b;Gould and Feiro 2005).…”

Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity

“…Furthermore, the proportion of variance between individuals that is accounted for by general abilities increases across the life span, accounting for as much as 80% of the variance between elderly individuals and only 40% ‫)%01ע(‬ among the rest of the population (Plomin and Spinath 2002). Despite the critical need to elucidate the basis for the impairment of general abilities, studies of age-related learning abilities in laboratory animals most often depend on single, limited, or idiosyncratic learning tasks (Gage et al 1984;Barnes and McNaughton 1985;Markowska et al 1994;Meliska et al 1997;Nalbantoglu et al 1997;Vogel et al 2002). Absent a strategy that is specifically sensitive to the general cognitive abilities of aged animals, a high proportion of the cognitive deficits that accrue with aging may go unexplained.…”