Summary Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer disease (AD) evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and co-aggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

The patterning of skeletal muscle is thought to depend upon signals provided by motor neurons. We show that AChR gene expression and AChR clusters are concentrated in the central region of embryonic skeletal muscle in the absence of innervation. Neurally derived Agrin is dispensable for this early phase of AChR expression, but MuSK, a receptor tyrosine kinase activated by Agrin, is required to establish this AChR prepattern. The zone of AChR expression in muscle lacking motor axons is wider than normal, indicating that neural signals refine this muscle-autonomous prepattern. Neuronal Neuregulin-1, however, is not involved in this refinement process, nor indeed in synapse-specific AChR gene expression. Our results demonstrate that AChR expression is patterned in the absence of innervation, raising the possibility that similarly prepatterned muscle-derived cues restrict axon growth and initiate synapse formation.

Soluble β-amyloid (Aβ) oligomers impair synaptic plasticity and cause synaptic loss associated with Alzheimer’s disease (AD). We report that murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain, are receptors for Aβ oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and in a transgenic model of AD, PirB not only contributed to memory deficits present in adult mice, but also mediated loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking LilrB2 function.

The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5 -regulatory region of BCL-6, a proto-oncogene encoding for a POZ͞Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or ref lect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5 -noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 ؋ 10 ؊4 ͞bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-GC phenotype and carrying mutated Ig variable heavy chain sequences. These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.Somatic hypermutation is one of the mechanisms by which Ig genes are modified in B cells to generate a large repertoire of B lymphocytes, each expressing a unique antibody molecule (1). This process is activated in germinal center (GC) B cells (2-4), where it introduces mutations in the variable region of Ig genes (IgV) at a frequency of 2-8 ϫ 10 Ϫ2 in humans (5). The mechanism involved in IgV hypermutation is not known, although experimental evidence suggests that it requires transcription of the target sequences and the presence of the Ig enhancer but not a specific promoter (6-8).It is generally assumed that the process of somatic hypermutation is restricted to the Ig loci including heavy and light chain variable region genes (1). However, B cell lymphomas were shown to display somatic hypermutation of the 5Ј-noncoding region of BCL-6 (9, 10), a proto-oncogene encoding a POZ͞Zinc finger transcriptional repressor normally expressed within GC B cells and required for GC formation (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). In 30% of diffuse large cell lymphoma (DLCL) and 5-10% of follicular lymphoma (FL), the BCL-6 gene is altered structurally by chromosomal translocations (11). In addition, mutations of its 5Ј-noncoding region were frequently found in DLCL and FL even in the absence of translocations involving this locus (9, 10). In most tumor cases, mutations were multiple, often biallelic, and clustered in the 5Ј regulatory sequences at frequencies (7 ϫ 10 Ϫ4 through 1.6 ϫ 10 Ϫ2 ͞bp) comparable with that of IgV genes in B cells (9). These findings raised the question of whether BCL-6 mutations represent a tumor associated misfunction or the effect of the IgV hypermutation process acting on non-Ig genes.To address this issue, we have investigated the presence of BCL-6 mutations in normal GC and naive B cells by...

No abstract

Sonic hedgehog signaling controls the differentiation of motor neurons in the ventral neural tube, but the intervening steps are poorly understood. A differential screen of a cDNA library derived from a single Shh-induced motor neuron has identified a novel homeobox gene, MNR2, expressed by motor neuron progenitors and transiently by postmitotic motor neurons. The ectopic expression of MNR2 in neural cells initiates a program of somatic motor neuron differentiation characterized by the expression of homeodomain proteins, by neurotransmitter phenotype, and by axonal trajectory. Our results suggest that the Shh-mediated induction of a single transcription factor, MNR2, is sufficient to direct somatic motor neuron differentiation.

IntroductionIn early stages of Alzheimer’s disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology.ResultsWe now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss.ConclusionsThese data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0199-x) contains supplementary material, which is available to authorized users.

Several imaging modalities are suitable for in vivo molecular neuroimaging, but the blood-brain barrier (BBB) limits their utility by preventing brain delivery of most targeted molecular probes. We prepared biodegradable nanocarrier systems made up of poly(n-butyl cyanoacrylate) dextran polymers coated with polysorbate 80 (PBCA nanoparticles) to deliver BBB-impermeable molecular imaging probes into the brain for targeted molecular neuroimaging. We demonstrate that PBCA nanoparticles allow in vivo targeting of BBBimpermeable contrast agents and staining reagents for electron microscopy, optical imaging (multiphoton), and whole brain magnetic resonance imaging (MRI), facilitating molecular studies ranging from individual synapses to the entire brain. PBCA nanoparticles can deliver BBB-impermeable targeted fluorophores of a wide range of sizes: from 500-Da targeted polar molecules to 150,000-Da tagged immunoglobulins into the brain of living mice. The utility of this approach is demonstrated by (i) development of a "Nissl stain" contrast agent for cellular imaging, (ii) visualization of amyloid plaques in vivo in a mouse model of Alzheimer's disease using (traditionally) non-BBB-permeable reagents that detect plaques, and (iii) delivery of gadolinium-based contrast agents into the brain of mice for in vivo whole brain MRI. Four-dimensional real-time two-photon and MR imaging reveal that brain penetration of PBCA nanoparticles occurs rapidly with a time constant of ∼18 min. PBCA nanoparticles do not induce nonspecific BBB disruption, but collaborate with plasma apolipoprotein E to facilitate BBB crossing. Collectively, these findings highlight the potential of using biodegradable nanocarrier systems to deliver BBB-impermeable targeted molecular probes into the brain for diagnostic neuroimaging.in vivo multiphoton imaging | transgenic mice T he ability to image structure and function in the brain using tools as diverse as multiphoton fluorescence imaging and magnetic resonance imaging (MRI) hold the promise of providing insight into physiology and pathophysiological conditions, but are greatly limited by the ability to deliver contrast agents with molecular specificity across the blood-brain barrier (BBB). Although several molecular imaging contrast agents targeted to structures of interest have been developed for research and clinical applications, only a small fraction of them cross the BBB, including amyloid binding dyes that required many years to develop (1-4). This leads to surprising gaps in the ability to monitor cells and cellular processes in the central nervous system (CNS), requiring skull burr holes and topical application to visualize agents ranging from simple molecular Nissl stains to highly specific antibodies (5-7). Multiple approaches have been developed to nonspecifically disrupt the BBB to allow BBB-impermeable targeted molecular imaging probes entrance into brain parenchyma, but these approaches induce uncontrolled neuronal injuries as well as allow circulating toxins and neuroactive agents to g...