Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer’s disease

Abstract

The synaptic changes underlying the onset of cognitive impairment in Alzheimer’s disease (AD) are poorly understood. In contrast to the well documented inhibition of long-term potentiation (LTP) in CA3-CA1 synapses by acute Aβ application in adult neurons from rodents, young amyloid precursor protein (APP) transgenic mouse models often, surprisingly, show normal LTP. This suggests that there may be important differences between mature-onset and developmental-onset APP expression/ Aβ accumulation and the ensuing synaptic and behavioural phenotype. Here, in agreement with previous studies, we observed that developmental expression of APP Sw,Ind (3–4 month old mice from line 102, PLoS Med 2:e355, 2005), resulted in reduced basal synaptic transmission in CA3-CA1 synapses, normal LTP, impaired spatial working memory, but normal spatial reference memory. To analyse early Aβ-mediated synaptic dysfunction and cognitive impairment in a more mature brain, we used controllable mature-onset APP Sw,Ind expression in line 102 mice. Within 3 weeks of mature-onset APP Sw,Ind expression and Aβ accumulation, we detected the first synaptic dysfunction: an impairment of LTP in hippocampal CA3-CA1 synapses. Cognitively, at this time point, we observed a deficit in short-term memory. A reduction in basal synaptic strength and deficit in long-term associative spatial memory were only evident following 12 weeks of APP Sw,Ind expression. Importantly, the plasticity impairment observed after 3 weeks of mature-onset APP expression is reversible. Together, these findings demonstrate important differences between developmental and mature-onset APP expression. Further research targeted at this early stage of synaptic dysfunction could help identify mechanisms to treat cognitive impairment in mild cognitive impairment (MCI) and early AD.

Reduction of NgR in perforant path decreases amyloid-β peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice

“…Thus, we investigated whether the downregulation of NgR could prevent impairments in synaptic plasticity in the hippocampus. LTP is widely considered to be one of the major cellular mechanisms of learning and memory [34]. In our study, it was induced by HFS in the CA1 region of 9-month-old TG-shNgR mice and TG-vector mice ( Fig.…”

Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

“…As no significant differences were found between the two control groups (i.e. WT and tTA), these control genotypes were treated equally and the data from these two groups was collapsed as one control group (Ctrl) [31].…”

“…As overexpression, and consequently, overproduction of APP and Aβ, occurs during brain development, this might affect the cell signalling and synapse formation, causing artificial phenotypes unrelated to AD pathology [4, 30]. Moreover, immature and mature mice might respond differently to the high exposure of sAβ species, making the neuronal circuits more sensitive or resilient to sAβ [31]. Therefore, it is crucial to evaluate the toxicity of sAβ oligomers on mature mice.…”

Mouse models of neurodegeneration: Know your question, know your mouse

“…In a number of situations, classical rodent assays of cognitive behavior may not always model the human cognitive process as intended (Figure 3). For example, do deficits in Morris watermaze performance in mouse models of neurodegeneration always indicate memory impairment (140)? Is working memory as studied in rodents undertaking a win-shift maze task (for example, the radial maze or T-maze task) really the equivalent of working memory in humans as studied, for example, in the Nback task or the digit span task (141)?…”

“…In addition, a battery of spatial memory tests also needs to be included to allow the generality of any findings from the watermaze swim test to be ascertained under different behavioral conditions that are unaffected by performance factors like thigmotaxis (continually swimming close to the side wall of the pool) and floating behavior. Both of these behaviors present confounds in watermaze studies conducted in mouse models of neurodegeneration (140). The distance that the platform is located from the side wall of the pool may thus be an important experimental variable in such studies (142).…”