Systematic Review of the Relationship between Amyloid-β Levels and Measures of Transgenic Mouse Cognitive Deficit in Alzheimer's Disease

Abstract

Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer’s disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical “side effect” of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively “high” levels of Aβ but are not quantitatively sensitive to the levels themselves.

Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease

“…Amyloidogenesis, ThT Fluorescence Assay-To measure amyloidogenesis of A␤40, A␤42, and A␤ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), ThT fluorescence assays were performed according to a previous report (38) with minor modifications. Briefly, a 10-l sample was mixed with a 2-ml ThT solution (10 M in 50 mM glycine-NaOH, pH 8.0), and fluorescence intensity was measured at wavelengths of 450 nm (excitation) and 482 nm (emission) using an RF-1500 fluo-rescence spectrophotometer (Shimadzu, Kyoto, Japan).…”

“…1C). Similarly, A␤42 and A␤ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), which are known to be more prone to aggregation compared with A␤40, were incubated with GAPDH aggregates for 1 h to demonstrate augmentation of ThT fluorescence (Fig. 1, D and E).…”

“…We then demonstrate that GAPDH aggregates potentiate A␤40-induced neurotoxicity, accompanied by mitochondrial dysfunction in vitro and in vivo. The triple transgenic mouse model of AD (3ϫTg-AD), which exhibits both intracellular and extracellular age-dependent A␤ aggregation (25), is often used in studies investigating AD pathogenesis (35). Therefore, we also examined the link between GAPDH aggregation and AD pathogenesis in 3ϫTg-AD mice.…”

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

“…Human AD patients often exhibit an increased rate of hippocampal volume loss, in comparison to age-matched controls (Thompson et al, 2004;Salat et al, 2011). Based on findings in studies of human Alzheimer's disease patients, mice with disruptions in various parts of the amyloid processing pathway have been developed to be used as models of Alzheimer's disease (Webster et al, 2014;Foley et al, 2014). Transgenic mouse models, which overexpress mutated forms of APP, have shown decreases in volume (Gonzalez-Lima et al, 2001), adult neurogenesis (Donovan et al, 2006), and an increase in neuronal loss (Schmitz et al, 2004) in the hippocampus.…”

Ontogenetic and Phylogenetic Approaches for Studying the Mechanisms of Cognitive Dysfunctions

“…This model still is most often used in AD research. Apart from accelerated formation of amyloid plaques and neurofibrillary tangles, these mice demonstrate other pathological and behavioral feature characteristics of AD, for example, synaptic impairment and memory deterioration [22]. For elucidating the role of aging in development of sporadic AD, a model of senescence accelerated mice has been developed, which demonstrates Aβ deposits and cognitive decline as early as 6 months of age [23].…”