Age-related evolution of amyloid burden, iron load, and MR relaxation times in a transgenic mouse model of Alzheimer's disease

Abstract

T1 and T2 magnetic resonance relaxation times have the potential to provide biomarkers of amyloid-beta deposition that could be helpful to the development of new therapies for Alzheimer's disease. Here, we measured T1 and T2 times as well as plaques and iron loads in APP/PS1 mice, which model brain amyloidosis, and control PS1 mice. Iron was mostly associated with amyloid deposits in APP/PS1 animals, while it was diffuse in the PS1 mice. T1 was negatively correlated with age in most structures in APP/PS1 animals. This may be related to the age-associated myelin loss described in APP/PS1 mice rather than to amyloid deposition. T2 in the subiculum of adult APP/PS1 animals was lower than in PS1 mice, which may be related to the very high amyloid and iron loads in this region. T2 in the subiculum could thus serve as an early marker of the amyloid pathology.

Human brain myelination and amyloid beta deposition in Alzheimer's disease

“…The PIB data show that in AD, Aβ deposition is also observed predominantly in late-myelinating regions [35][36][37] (Figure 1A, C). We hypothesized that myelin breakdown in vulnerable late-myelinating regions ( Figure 1B, D) releases oligodendrocyte-and myelin-associated iron [19,21,28,38,39], thus promoting Aβ oligomerization, its associated toxicity, and deposition of oligomerized Aβ and iron in neuritic plaques [7,28,[40][41][42][43] (Figure 1A, C). This hypothesis has been supported in transgenic mouse models that demonstrated increased vulnerability of oligodendrocytes to toxicity [44], agerelated white matter volume reductions [45], and age-related iron deposition in amyloid plaques [42].…”

“…We hypothesized that myelin breakdown in vulnerable late-myelinating regions ( Figure 1B, D) releases oligodendrocyte-and myelin-associated iron [19,21,28,38,39], thus promoting Aβ oligomerization, its associated toxicity, and deposition of oligomerized Aβ and iron in neuritic plaques [7,28,[40][41][42][43] (Figure 1A, C). This hypothesis has been supported in transgenic mouse models that demonstrated increased vulnerability of oligodendrocytes to toxicity [44], agerelated white matter volume reductions [45], and age-related iron deposition in amyloid plaques [42]. Human studies have likewise confirmed age-related myelin breakdown that is exacerbated in healthy APOE e4 carriers and AD subjects [7,43] and age-related increases in brain iron [21] that are exacerbated in AD subjects [28].…”

“…Transgenic mouse models as well as human studies have demonstrated that a strong association exists between tissue iron and the production of senile plaques [28,[40][41][42]. Myelin and oligodendrocytes have the highest iron content of brain tissues.…”

“…The percentage of dry brain weight in humans accounted for by myelin is 30% higher than in rodents [48], and it is thus not surprising that rodents have much lower levels of brain iron (up to an order of magnitude) than humans [24,49,50]. Iron levels increase with age in both species [21,23,24,42,50]. These age-related increases might contribute to both the age-related increase in amyloid plaques observed in both species [14,41,42] and the correlation between tissue iron and amyloid deposit load observed in late-myelinating regions [14,42] that are most vulnerable to myelin breakdown and the release of iron [3,7,21,28,43].…”

“…These regions contain predominantly thinly myelinated fibers with smaller axons and thus contain an increased proportion of myelin [9,43]. The age-related loss of myelin from primarily these thinly myelinated small axons (estimated at 10% per decade [13]) would take a disproportionate toll in late-myelinating regions and make much higher iron levels available for interaction with Aβ and deposition in amyloid plaques in these regions [41,42].…”