Aβ and tau prions feature in the neuropathogenesis of Down syndrome

Abstract

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

Keywords: Aβ; Down syndrome; cellular bioassays; prions; tau.

Fig. 1.

Cell bioassays detect Aβ and tau prions in DS brain samples. (A) Diluted (0.03×) PTA extracts from frozen brain samples of adults with DS were added to HEK293T cells expressing YFP–Aβ42 or tau–YFP to measure Aβ and tau prion infectivity, respectively. Cell-based prion infectivity measurements plotted as a function of the donor age at death. Data are presented as the mean and SD of four technical replicates per individual subject per assay. PBS control refers to the vehicle buffer with lipofectamine that is used in the cell infection protocol. (B) Bar graphs showing group comparison of Aβ and tau prion infectivity for DS and cognitively neurotypical, age-matched controls. Data are presented as the mean and SD of all samples per group. Aβ prion infectivity values are as follows: 1) DS = 151,420 arbitrary units (a.u.) ± 64,311; 2) aged control = 5,522 a.u. ± 3,594. Tau prion infectivity values are as follows: 1) DS = 189,912 a.u. ± 80,154; 2) aged control = 2,980 a.u. ± 3,131. Student’s t test was used to assess statistical significance compared with aged controls. (C) Tau prion infectivity was plotted as a function of Aβ prion infectivity for each sample with DS, and a linear regression was performed. Individuals with DS who were ≥40 y old (filled circles) and those who were younger than 40 y (open circles) were plotted together. y.o., years old.

Fig. 2.

Cell bioassays detect Aβ and tau prions in fAD and sAD brain samples. (A) Diluted (0.03×) PTA extracts from frozen fAD and sAD brain samples were added to HEK293T cells expressing YFP–Aβ42 or tau–YFP to measure Aβ and tau prion infectivity, respectively. Cell-based prion infectivity measurements plotted as a function of the donor age at death. Data are presented as the mean and SD of four technical replicates per individual subject per assay. PBS control refers to the vehicle buffer with lipofectamine that is used in the cell infection protocol. (B) Bar graphs showing group comparison of Aβ and tau prion infectivity for fAD, sAD, and cognitively normal, age-matched controls. Data are presented as the mean and SD of all samples per group. Aβ prion infectivity values are as follows: 1) sAD = 112,557 arbitrary units (a.u.) ± 59,276; 2) fAD APP = 143,570 a.u. ± 76,647; 3) fAD PSEN1 = 135,387 a.u. ± 61,832; 4) fAD PSEN2 = 54,358 a.u. ± 22,782; and 5) aged control = 7,439 a.u. ± 3,143. Tau prion infectivity values are as follows: 1) sAD = 113,925 a.u. ± 34,152; 2) fAD APP = 147,827 a.u. ± 60,521; 3) fAD PSEN1 = 135,374 a.u. ± 56,701; 4) PSEN2 = 68,340 a.u. ± 45,068; and 5) aged control = 9,254 a.u. ± 5,717. A two-way ANOVA with Tukey’s multiple comparison test was used to assess statistical significance compared with aged controls. Comparisons between all groups were made, but only comparisons that reached statistical significance are annotated on the graph. (C) Tau prion infectivity was plotted as a function of Aβ prion infectivity for each fAD and sAD donor, and a linear regression was performed.

Fig. 3.

Aβ and tau prion abundance increases with age in DS but not in AD. (A and B) Aβ and tau prion infectivity in DS brain samples plotted as a function of donor age at death. (C and D) Aβ and tau prion infectivity in fAD (filled symbols) and sAD (open symbols) brain samples plotted as a function of donor age at death. Linear regression was performed in all panels.