The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease

Abstract

Transgenic mice expressing mutant amyloid precursor proteins (APPs) have provided important new information about the pathogenesis of Alzheimer's disease (AD) histopathology. However, the molecular basis of memory loss in these mice is poorly understood. One of the major impediments has been the difficulty of distinguishing between age-dependent and ageindependent behavioral changes. To address this issue we studied in parallel two lines of APP transgenic mice expressing comparable levels of mutant and wild-type human APP. This enabled us to identify age-independent behavioral deficits that were not specifically related to mutant APP expression. When mice with age-independent deficits were eliminated, we detected memory loss in transgenic mice expressing mutant APP (Tg2576 mice) starting at ϳ6 months, which coincided with the appearance of detergent-insoluble A␤ aggregates (A␤ insol ). Genetically accelerating the formation of A␤ insol resulted in an earlier onset of memory decline. A facile interpretation of these results, namely that memory loss and A␤ insol were closely connected, was rejected when we extended our analysis to include older mice. No obvious correspondence between memory and A␤ insol was apparent in a combined group of old and young mice unless the mice were stratified by age, whereupon inverse correlations between memory and A␤ insol became evident. These results suggested that A␤ insol is a surrogate marker for small assemblies of A␤ that disrupt cognition and occur as intermediates during A␤ insol formation, and they are the first descriptive in vivo data supporting their role in impairing memory. These studies also provide a methodological framework within which to investigate these A␤ assemblies in vivo.

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

“…These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is responsible for age-related memory decline in this model [15][16][17] .…”

“…These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is responsible for age-related memory decline in this model [15][16][17] .By means of several experimental approaches, we demonstrate an increase of caspase-3 activity in Tg2576 hippocampal synapses at 3 months of age, much earlier than amyloid plaque deposition is detectable 11 . We report that this enhanced local caspase-3 activity leads to a permanent activation of calcineurin which causes, in turn, AMPA receptor (AMPAR) GluR1 subunit dephosphorylation and its removal from the post-synaptic sites.…”

Unconventional ligands and modulators of nicotinic receptors

“…However, it has been reported that there does not seem to be a direct, simple correlation between levels of insoluble (i.e., aggregated) A␤ and cognitive deficits observed in transgenic mice that express a mutant form of human APP. It appears that soluble forms of A␤ correlate better with the cognitive declines observed in these mice (Westerman et al, 2002).…”

Impact of amyloid imaging on drug development in Alzheimer's disease

“…In summary, the evidence that oligomeric Aβ42 is the most toxic species of Aβ is convincing. Studies strongly support the following: 1) all else being equal, enriched oligomeric preparations of Aβ42 appear to be the most toxic species [38,39]; 2) oligomeric species of Aβ42 can inhibit long term potentiation (LTP) and lead to synaptic dysfunction [48,49]; 3) memory loss occurs prior to extensive deposition of fibrillar Aβ42 in transgenic mice and can be reversed by targeting soluble species of Aβ42 [50,51,52,53]; and 4) oligomeric Aβ42 species exist in AD brain [54]. However, it is important to appreciate that the removal or reduction of the soluble, toxic oligomeric forms of Aβ42 from brain parenchyma will require the concomitant reduction and removal of the insoluble (fibrillar) Aβ42 pool as well.…”

“…In Tg2576 mice, no obvious correspondence between memory and insoluble Aβ levels was apparent [53]. Furthermore, passive immunization studies of this same Tg2576 strain of mice showed that memory deficits and disruption of LTP can be reversed without affecting the levels of soluble or insoluble Aβ, suggesting "neutralization" of soluble Aβ by antibodies may be sufficient to aid in cognitive improvement [51,52].…”