Transmission and spreading of tauopathy in transgenic mouse brain

Abstract

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease 1. In the disease process neuronal tau inclusions first appear in transentorhinal cortex, from where they appear to spread to hippocampal formation and neocortex 2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. Abundant tau inclusions, in the absence of β-amyloid deposits, define Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases 1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia 3-5. Thus, transgenic mice expressing mutant (e.g. P301S) human tau in nerve cells exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein 6,7. In contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or display neurodegeneration 7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that the injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces the assembly of wild-type human tau into filaments and the spreading of pathology from the site of injection to neighbouring brain regions.

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

“…the intercellular transfer of misfolded proteins has recently been demonstrated in several neurodegenerative diseases, including aLS [1][2][3], and it has been suggested that this mechanism is responsible for the progressive spread of pathology. Mutations in SOD1 (Cu/Zn-superoxide dismutase) cause 20 % of familial aLS, and these cases display similar clinical features and pathogenesis to sporadic aLS, which accounts for 90 % of all aLS cases.…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…Two-way ANOVA revealed no significant main effect for day (F (2, 162) = 2.221, P = 0.1118) and genotype (F (2, 162) = 1.862, P = 0.1587) during the A2 task (Figure 4f). On the P2 probe trial, the analysis of the percentage of time spent in the four quadrants revealed a significant main effect for quadrant (F (3,162) = 78.21, P o0.0001), no significant main effect for genotype (F (2,54) = 0.3026, P = 0.7402) but a significant quadrant × genotype interaction (F (6, 162) = 2.935, P = 0.0096) (Figure 4g). Post hoc Tukey's multiple comparisons test showed that the Tau DN/WT mice spend significantly less time in the target quadrant as compared with littermates ( Figure 4g).…”

“…Recent data suggest that a fraction of Tau protein is localized extracellularly. [1][2][3][4] However, the biological function of extracellular tau is unknown.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…Injection of brain lysate containing aggregated forms of tau into mice that express WT human tau induced the formation of neurofibrillary tangles in the recipient mice. These spread beyond the injected hippocampus to more distant sites, including somatosensory cortex [43]. Immuno-depletion of tau from the injected material prevented induction of neurofibrillary tangles, confirming tau, and not a nonspecific "toxic factor" as the cause of pathology.…”

“…Immuno-depletion of tau from the injected material prevented induction of neurofibrillary tangles, confirming tau, and not a nonspecific "toxic factor" as the cause of pathology. Finally, injection of P301S-containing brain lysate into mice that only express murine tau produced very limited pathology that was confined to the injection site [43]. This was reminiscent of the seeding barriers observed for PrP.…”