Brain Region-Specific Differences in Amyloid-β Plaque Composition in 5XFAD Mice

Abstract

Senile plaques consisting of amyloid-beta (Aβ) peptides are a major pathological hallmark of Alzheimer’s disease (AD). Aβ peptides are heterogeneous regarding the exact length of their amino- and carboxy-termini. Aβ1-40 and Aβ1-42 are often considered to represent canonical “full-length” Aβ species. Using immunohistochemistry, we analyzed the distribution of Aβ1-x, Aβx-42 and Aβ4-x species in amyloid deposits in the subiculum, hippocampus and cortex in 5XFAD mice during aging. Overall plaque load increased in all three brain regions, with the subiculum being the area with the strongest relative plaque coverage. In the subiculum, but not in the other brain regions, the Aβ1-x load peaked at an age of five months and decreased thereafter. In contrast, the density of plaques positive for N-terminally truncated Aβ4-x species increased continuously over time. We hypothesize that ongoing plaque remodeling takes place, leading to a conversion of deposited Aβ1-x peptides into Aβ4-x peptides in brain regions with a high Aβ plaque burden.

Cytokine expression patterns predict suppression of vulnerable neural circuits in a mouse model of Alzheimer’s disease

“…One feature to note is that month 1.5 and month 2 exhibit different anatomical network profiles even though both timepoints are associated with the early stage of disease development ( Figure 3A ). There is cerebral accumulation of Amyloid plaques that at months 1.5 and 2 (42, 43). However, the difference in concentration between the two points is steep and so month 2 can be used as a proxy to describe a later stage in disease development (43) relative to month 1.5.…”

“…There is cerebral accumulation of Amyloid plaques that at months 1.5 and 2 (42, 43). However, the difference in concentration between the two points is steep and so month 2 can be used as a proxy to describe a later stage in disease development (43) relative to month 1.5. This feature is reflected in how markedly different the two anatomical networks are, where there is a clear difference in the number of depressed anatomical connectivity values for 5xFAD versus the control ( Figure 3A,B ).…”

“…One potential reason for this would be that both regions feature efferent connections from the cortex (114, 122, 126). This feature is important since intraneuronal amyloid beta accumulates in the cortex of 5xFAD mice at months 1.5 (43), leading to a potential spillover to brain regions that have bijective connections to the afflicted cortical regions; like the Thalamus and Basal Ganglia.…”

“…Our results reflect similarities in these global metrics in aging, but the difference at the terminal time point could be explained by how healthy aging brains may be able to compensate for age-related functionality declines (136, 137). It is extremely likely that the diseased brain is unable to undertake such processes given the breadth of tissue damage as a result of chronic inflammation due to disease pathology (43, 64, 86, 129-132, 138).…”

“…There is cerebral accumulation of Amyloid plaques that at months 1.5 and 2 (42,43). However, the difference in concentration between the two points is steep and so month 2 can be used as a proxy to describe a later stage in disease development (43) relative to month 1.5.…”