High Levels of β-Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse

Abstract

Alzheimer’s Disease (AD) is the most common Neurodegenerative Disease (ND), primarily characterised by neuroinflammation, neuronal plaques of β-amyloid (Aβ), and neurofibrillary tangles of hyperphosphorylated tau. α-Synuclein (α-syn) and its heteroaggregates with Aβ and tau have been recently included among the neuropathological elements of NDs. These pathological traits are not restricted to the brain, but they reach peripheral fluids as well. In this sense, Red Blood Cells (RBCs) are emerging as a good model to investigate the biochemical alterations of aging and NDs. Herein, the levels of homo- and heteroaggregates of ND-related proteins were analysed at different stages of disease progression. In particular, a validated animal model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone) and its control strain SAMR1 (Senescence-Accelerated Mouse-Resistant) were used in parallel experiments. The levels of the aforementioned proteins and of the inflammatory marker interleukin-1β (IL-1β) were examined in both brain and RBCs of SAMP8 and SAMR1 at 6 and 8 months. Brain Aβ, tau, and phospho-tau (p-tau) were higher in SAMP8 mice than in control mice and increased with AD progression. Similar accumulation kinetics were found in RBCs, even if slower. By contrast, α-syn and its heterocomplexes (α-syn-Aβ and α-syn-tau) displayed different accumulation kinetics between brain tissue and RBCs. Both brain and peripheral IL-1β levels were higher in SAMP8 mice, but increased sooner in RBCs, suggesting that inflammation might initiate at a peripheral level before affecting the brain. In conclusion, these results confirm RBCs as a valuable model for monitoring neurodegeneration, suggesting peripheral Aβ, tau, and p-tau as potential early biomarkers of AD.

Prodromal Intestinal Events in Alzheimer’s Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition

“…With regard to the assessment of AD-related protein heterocomplexes, we found an increase in the levels of α-syn-Aβ and α-syn-tau deposits in colonic tissues from SAMP8, suggesting that enteric Aβ and tau accumulation could increase their interaction with α-syn. These results are in line with our previous findings showing increased levels of α-syn-Aβ and α-syn-tau heterocomplexes in the brain and red blood cells from SAMP8 mice at six months [25]. Moreover, we observed an increase in IL-1β levels in colonic tissues from SAMP8 animals, suggesting the occurrence of inflammatory responses in the large bowel of early AD mice.…”

“…SAMP8 mice displayed an increase in faecal Aβ as well as colonic Aβ and p-tau levels, as compared with controls. These findings reflect Aβ and p-tau accumulation detected in brain tissues from SAMP8 at six months in previous studies, and suggest that AD-related protein deposits in intestinal tissues correlate with those detected in the brain from SAMP8 mice at early stages of the disease [25,29]. By contrast, no variation of colonic total and oligomeric α-syn levels were found when comparing SAMP8 and SAMR1 animals.…”

“…The SAMP8 mouse develops spontaneously early learning and memory deficits, with similar features to those observed in AD patients. Of interest, the SAMP8 mouse, which develops a severe disease after eight months of age, can be an extremely valuable model to investigate intestinal symptoms in the prodromal stage of AD [13,14,25].…”

α-Synuclein heteromers with ß-amyloid and tau decreased in red blood cells of Alzheimer’s disease and Lewy Body dementia patients.

“…Interestingly, their expression levels and aggregation processes are not restricted to the brain, but reach peripheral compartments, possibly con guring a systemic disease [35,50]. Among peripheral cells, RBCs were demonstrated to be particularly susceptible to the oxidative stress and accumulation of misfolded proteins [25,31,33,[51][52][53][54]. Herein, a cohort of AD and LBDs patients and a group of HCs were recruited to quantify the RBCs concentrations of α-syn and its heterocomplexes with tau and Aβ 1−42 , and to test their potential discriminatory accuracy.…”

Apolipoprotein E polymorphism and oxidative stress in human peripheral blood cells: can physical activity reactivate the proteasome system through epigenetic mechanisms?

“…The oxidative stress initiates and enhances the accumulation and aggregation of Aβ in the brain of AD patients [8,9]. To this regard, Aβ has been recently demonstrated to also accumulate in erythrocytes [18,[37][38][39]. On this basis, Aβ accumulation was measured in erythrocytes of the enrolled subjects.…”