Neurobiology
Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy
Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable with what is observed in Alzheimer’s disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, because bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, the full-length lung and endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau triggers neuronal tau aggregation.Truncation of Tau selectively facilitates its pathological activities
Neurofibrillary tangles of abnormally hyperphosphorylated Tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. Although many studies have reported the effect of truncation on the aggregation of Tau, these studies mostly employed highly artificial conditions, using heparin sulfate or arachidonic acid to induce aggregation. Here, we report for the first time the pathological activities of various truncations of Tau, including site-specific phosphorylation, self-aggregation, binding to hyperphosphorylated and oligomeric Tau isolated from AD brain tissue (AD O-Tau), and aggregation seeded by AD O-Tau.An RNA aptamer with potent affinity for a toxic dimer of amyloid β42 has potential utility for histochemical studies of Alzheimer's disease
Oligomers of β-amyloid 42 (Aβ42), rather than fibrils, drive the pathogenesis of Alzheimer's disease (AD). In particular, toxic oligomeric species called protofibrils (PFs) have attracted significant attention. Herein, we report RNA aptamers with higher affinity toward PFs derived from a toxic Aβ42 dimer than toward fibrils produced from WT Aβ42 or from a toxic, conformationally constrained Aβ42 variant, E22P–Aβ42. We obtained these RNA aptamers by using the preincubated dimer model of E22P–Aβ42, which dimerized via a linker located at Val-40, as the target of in vitro selection.Compound screening in cell-based models of tau inclusion formation: Comparison of primary neuron and HEK293 cell assays
The hallmark pathological features of Alzheimer’s disease (AD) brains are senile plaques, comprising β-amyloid (Aβ) peptides, and neuronal inclusions formed from tau protein. These plaques form 10–20 years before AD symptom onset, whereas robust tau pathology is more closely associated with symptoms and correlates with cognitive status. This temporal sequence of AD pathology development, coupled with repeated clinical failures of Aβ-directed drugs, suggests that molecules that reduce tau inclusions have therapeutic potential.Impaired tau–microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations
tau is a microtubule (MT)-associated protein that promotes tubulin assembly and stabilizes MTs by binding longitudinally along the MT surface. tau can aberrantly aggregate into pathological inclusions that define Alzheimer's disease, frontotemporal dementias, and other tauopathies. A spectrum of missense mutations in the tau-encoding gene microtubule-associated protein tau (MAPT) can cause frontotemporal dementias. tau aggregation is postulated to spread by a prion-like mechanism. Using a cell-based inclusion seeding assay, we recently reported that only a few tau variants are intrinsically prone to this type of aggregation.Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?
The histopathology of Alzheimer's disease (AD) is characterized by neuronal loss, neurofibrillary tangles, and senile plaque formation. The latter results from an exacerbated production (familial AD cases) or altered degradation (sporadic cases) of 40/42-amino acid–long β-amyloid peptides (Aβ peptides) that are produced by sequential cleavages of Aβ precursor protein (βAPP) by β- and γ-secretases. The amyloid cascade hypothesis proposes a key role for the full-length Aβ42 and the Aβ40/42 ratio in AD etiology, in which soluble Aβ oligomers lead to neurotoxicity, tau hyperphosphorylation, aggregation, and, ultimately, cognitive defects.Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies
The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases.An acetylation–phosphorylation switch that regulates tau aggregation propensity and function
The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau's biophysical properties in vitro. Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue.Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons: EVIDENCE FOR DIVERGENT LOSS-OF-FUNCTION AND “OFF-PATHWAY” CELLULAR MECHANISMS
Doublecortin on the X-chromosome (DCX) is a neuronal microtubule-binding protein with a multitude of roles in neurodevelopment. In humans, DCX is a major genetic locus for X-linked lissencephaly. The best studied defects are in neuronal migration during corticogenesis and in the hippocampus, as well as axon and dendrite growth defects. Much effort has been directed at understanding the molecular and cellular bases of DCX-linked lissencephaly. The focus has been in particular on defects in microtubule assembly and bundling, using knock-out mice and expression of WT and mutant Dcx in non-neuronal cells.The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1–42 Species into Nontoxic Amyloid Fibers with Altered Properties
Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity.Templated Aggregation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Seeding with TDP-43 Peptide Fibrils
TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as the major component of ubiquitin-positive neuronal and glial inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Aggregation of TDP-43 to amyloid-like fibrils and spreading of the aggregates are suggested to account for the pathogenesis and progression of these diseases. To investigate the molecular mechanisms of TDP-43 aggregation, we attempted to identify the amino acid sequence required for the aggregation.The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation
Background: The cytosolic ArPIKfyve-Sac3 complex binds PIKfyve to regulate housekeeping endosomal functions but other tissue-specific interactors and functions are unknown.Results: Brain Synphilin-1 is a novel interaction partner of the ArPIKfyve-Sac3 complex.Conclusion: The ArPIKfyve-Sac3 complex is an effective inhibitor of aggregate formation by Synphilin-1.Significance: The novel molecular means for reducing cytoplasmic aggregates of Synphilin-1 provides new insights into neurodegeneration mechanisms.
