Severe oligomeric tau toxicity can be reversed without long-term sequelae.

Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer's disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though P301S tau expression is maintained. Whereas various strategies to target tau aggregation have been developed, little is known about the long-term consequences of reverted tau toxicity. Therefore, we studied the long-term motor fitness of recovered, formerly paralysed P301SxTAU62on-off mice. To assess the seeding competence of oligomeric toxic tau species, we also inoculated ALZ17 mice with brainstem homogenates from paralysed P301SxTAU62on mice. Counter-intuitively, after recovery from paralysis due to oligomeric tau species expression, ageing P301SxTAU62on-off mice did not develop more motor impairment or tau pathology when compared to heterozygous P301S tau transgenic littermates. Thus, toxic tau species causing extensive neuronal dysfunction can be cleared without inducing seeding effects. Moreover, these toxic tau species also lack long-term tau seeding effects upon intrahippocampal inoculation into ALZ17 mice. In conclusion, tau species can be neurotoxic in the absence of seeding-competent tau aggregates, and mice can clear these tau forms permanently without tau seeding or spreading effects. These observations suggest that early targeting of non-fibrillar tau species may represent a therapeutically effective intervention in tauopathies. On the other hand, the absent seeding competence of early toxic tau species also warrants caution when using seeding-based tests for preclinical tauopathy diagnostics.

Cerebrospinal fluid from Alzheimer's disease patients promotes tau aggregation in transgenic mice.

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer's disease (AD). Tau derived from AD patients' brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models.Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential. CSF was injected intrahippocampally into young P301S tau transgenic mice. CSF obtained from AD or MCI patients increased hippocampal tau hyperphosphorylation and tau tangle formation in these mice at 4 months post-seeding. Tau pathology was also accentuated in the contralateral hippocampus, and in anterior and posterior directions, indicative of spreading.We provide first evidence for in vivo prion-like properties of AD patients' CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD. Further studies may help to evaluate strain specific properties of CSF derived tau bioseeds, and to assess their diagnostic potential.

Amyloid-ß in the Cerebrospinal Fluid of APP Transgenic Mice Does not Show Prion-like Properties.

Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-ß (Aß) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been shown that Aß derived from amyloid-containing brain tissue has prion-like properties: it induces misfolding and aggregation of Aß when injected into human amyloid precursor protein (APP) transgenic mice. In contrast, Aß in the CSF has been less studied, and it is not clear whether it also exhibits prion-like characteristics, which might provide a sensitive diagnostic tool. Therefore, we collected CSF from APP transgenic mice carrying the Swedish mutation (APP23 mice), and injected it intracerebrally into young mice from the same transgenic line. We found that CSF derived Aß did not induce increased ß-amyloidosis, even after long incubation periods and additional concentration. This suggests that Aß present in the CSF does not have the same prion-like properties as the Aß species in the brain.

Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease.

There is pivotal evidence that tau pathology can be triggered by amyloid-ß (Aß) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Aß aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model.

Patterning mechanisms and morphological diversity of spider appendages and their importance for spider evolution.

The prosoma of spiders bears different gnathal (labrum, chelicerae, pedipalps) and locomotory appendages (legs). In most species these appendages are also used for additional functions, e.g. sensing, mating, and courtship. The opisthosoma is equipped with four pairs of highly specialized appendages. Two pairs of spinnerets are used for silk production and manipulation. The other two pairs of appendages are internalized during development and give rise to a complex respiratory system of book lungs and tracheae. Thus spiders have a number of different appendage types with radically different adult morphologies. Furthermore, all these appendage types display significant additional species specific diversity correlating with a large spectrum of functions of the appendages. Despite this importance of appendage diversity for the evolution of the spiders we know relatively little about the genetic patterning mechanisms producing this diversity of morphology. We review recent advances concerning the developmental genetics of spider appendage diversification, mainly concentrating on open questions and future directions of research. We conclude that the deeper understanding of appendage development and diversity in spiders can contribute significantly not only to evolutionary developmental biology, but also to behavioral biology, speciation research and population genetics, and the study of sexually dimorphic traits.