Differences in Tau Seeding in Newborn and Adult Wild-Type Mice

Abstract

Alzheimer’s disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice.

Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice

“…Moreover, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct globular morphology [89]. Interestingly, globular neuronal inclusions were also reproduced in our hTau mice using the same inoculum and protocols as those employed in the inoculation of WT mice, in which no globular inclusions were detected [62].…”

“…The hippocampus of WT mice was not stained with anti-3Rtau antibodies except for polymorphic cells of the inner region of the DG, as detailed in a previous study [62]. In contrast, 3Rtau immunoreactivity in the neuropil and neuronal cytoplasm was marked in hTau mice.…”

“…Sarkosyl-insoluble fractions from GGT homogenates inoculated in the hippocampus and corpus callosum in WT mice produce phospho-tau seeding and spreading in neurons, threads, and oligodendroglial cells [57,62]. Neuronal deposits are reminiscent of pre-tangles, and inclusions in oligodendrocytes are coiled bodies; however, glial globular inclusions are absent [62].…”

“…A significant conclusion in the majority of the studies carried out on inoculated mice is that tau seeding and spreading are mainly dependent on the inoculated tau strain, and that tau deposits in the host are reminiscent of those seen in the corresponding human diseases [19,[49][50][51][52][53][54][55][56]. However, deposits in oligodendrocytes forming coiled bodies are found following the inoculation of tauopathies, as well as following the inoculation of AD and primary age-related tauopathy (PART) [57]; neuronal deposits are generated following the inoculation of pure cases of aging-related tau astrogliopathy (ARTAG) [58]; cellular deposits are not invariably disease-specific following the inoculation of homogenates from AD and tauopathies, at least in some experiments on WT mice [59][60][61]; and tau seeding and spreading differs in newborn and adult mice [62]. Disparities can be due, in part, to differences between murine and human tau [63,64].…”

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer’s disease inPrnpmutant mice and in the P301S transgenic tauopathy mice model

“…Thus, after the inoculation of ptau-containing samples in mice brains, pathologic ptau aggregates emerged both at the injection sites and in connected brain regions (e.g., [34, 41]). Thus, this approach has been used to elucidate the mechanisms of cell uptake, seeding and brain propagation of different tau species (oligomeric or fibrillar) as well the role of the endogenous tau in these processes (e.g., [8, 48, 51, 52, 90]). However, a complete explanation of these processes is unavailable for all tau isoforms and different tauopathies [64] especially when affected cells are other than neurons [45].…”