Retrograde BMP signaling at the synapse: a permissive signal for synapse maturation and activity-dependent plasticity.

At the Drosophila neuromuscular junction (NMJ), the loss of retrograde, trans-synaptic BMP signaling causes motoneuron terminals to have fewer synaptic boutons, whereas increased neuronal activity results in a larger synapse with more boutons. Here, we show that an early and transient BMP signal is necessary and sufficient for NMJ growth as well as for activity-dependent synaptic plasticity. This early critical period was revealed by the temporally controlled suppression of Mad, the SMAD1 transcriptional regulator. Similar results were found by genetic rescue tests involving the BMP4/5/6 ligand Glass bottom boat (Gbb) in muscle, and alternatively the type II BMP receptor Wishful Thinking (Wit) in the motoneuron. These observations support a model where the muscle signals back to the innervating motoneuron's nucleus to activate presynaptic programs necessary for synaptic growth and activity-dependent plasticity. Molecular genetic gain- and loss-of-function studies show that genes involved in NMJ growth and plasticity, including the adenylyl cyclase Rutabaga, the Ig-CAM Fasciclin II, the transcription factor AP-1 (Fos/Jun), and the adhesion protein Neurexin, all depend critically on the canonical BMP pathway for their effects. By contrast, elevated expression of Lar, a receptor protein tyrosine phosphatase found to be necessary for activity-dependent plasticity, rescued the phenotypes associated with the loss of Mad signaling. We also find that synaptic structure and function develop using genetically separable, BMP-dependent mechanisms. Although synaptic growth depended on Lar and the early, transient BMP signal, the maturation of neurotransmitter release was independent of Lar and required later, ongoing BMP signaling.

Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer's disease.

AßpE3-42 (N-terminal truncated amyloid-ß peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AßpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes.

N-truncated amyloid ß (Aß) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.

N-truncated Aß4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aß peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aß4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aß4-42 is as toxic as pyroglutamate Aß3-42 and Aß1-42. In line with these findings, treatment of wildtype mice using intraventricular Aß injection induced significant working memory deficits with Aß4-42, pyroglutamate Aß3-42 and Aß1-42. Transgenic mice expressing Aß4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aß4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aß4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.

HDAC1 regulates fear extinction in mice.

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.

Pyroglutamate amyloid ß (Aß) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

Pyroglutamate-modified Aß peptides at amino acid position three (Aß(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aß(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aß(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aß(pE3-42). TBA42 mice showed age-dependent behavioral deficits and Aß(pE3-42) accumulation. The Aß profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aß peptides: Aß(1-42), Aß(1-40), Aß(pE3-40), Aß(pE3-42), Aß(3-42), Aß(4-42), and Aß(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that Aß(pE3) levels were elevated in FAD42 mice. No change in Aß(x)(-42) or other Aß isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aß(pE-42) in FAD42 mice.

A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories.

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.

Altered histone acetylation is associated with age-dependent memory impairment in mice.

As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.