α-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease.

Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies.

Altered distribution of RhoA in Alzheimer's disease and AbetaPP overexpressing mice.

RhoGTPases control cytoskeleton dynamics thereby modulating synaptic plasticity. Because Alzheimer's disease (AD) is characterized by synaptic dysfunction, we sought to determine whether the expression, activity, or localization of the GTPases RhoA, Rac1 and Cdc42, as well as p21-PAK, a downstream target of Rac1/Cdc42, were altered in 18-month-old AbetaPP Tg2576 mice (Swedish mutation) or in brains from patients with AD and, for comparison in the case of RhoA, Pick's disease (PiD), a neurodegenerative disorder characterized by hyper-phosphorylated tau accumulation. Immunohistochemical analyses revealed a distinct localization of each RhoGTPase in synapses, dendrite shafts, neuronal bodies, or astrocytes.

Tau-knockout mice show reduced GSK3-induced hippocampal degeneration and learning deficits.

It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic mice that overexpress GSK3beta in forebrain regions including dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that GSK3 overexpression results in DG degeneration.

Kainic acid intraocular injections during the postnatal critical period induce plastic changes in the visual system.

Changes in the retino-collicular projection and in the number of optic nerve (ON) axons in adult rats were analyzed after partial loss of retinal ganglion cells (RGCs), induced by intravitreal injections of kainic acid (KA) on postnatal days 2-3 (P2-P3) or 10-12 (P10-P12). KA injected at P2-P3 decreased the volume of the adult contralateral superior colliculus (SC) and the density of the retino-collicular contralateral projection, but maintained the neonatal pattern in the ipsilateral projection from the un-injected eye. ON axon number was significantly increased in the un-injected eye but decreased in the KA-injected eye.

Phosphorylated tau in neuritic plaques of APP(sw)/Tau (vlw) transgenic mice and Alzheimer disease.

We have previously reported that double-transgenic APP(SW)/Tau(VLW) mice show enhanced amyloid deposition, stronger tau hyperphosphorylation, increased sarkosyl tau polymers, and wider tau filaments when compared to simple mutant models. To validate these transgenic mice as models of Alzheimer disease pathology, in the present study we analyze tau phosphorylation at 12E8 and AT-8 epitopes in amyloid plaques. In APP(SW) mice, phospho-tau in plaque-associated neurites suggests a local direct effect of plaque-amyloid (and/or APP(SW)) on tau phosphorylation.

Ultrastructural localization of intraneuronal Abeta-peptide in Alzheimer disease brains.

Autopsied brain tissue from Alzheimer's disease patients and old non-demented controls was studied after immunocytochemistry with the 4G8 monoclonal antibody that recognizes amyloid-beta peptides. Intraneuronal 4G8-positive reaction product was detected in all of the studied brains. The same brain regions in the Alzheimer's disease samples consistently showed both more immunopositive neurons and more stained reaction product per neuron than those from the non-demented brains.

Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain.

In Huntington's disease (HD), as in the rest of CAG triplet-repeat disorders, the expanded polyglutamine (polyQ)-containing proteins form intraneuronal fibrillar aggregates that are gathered into inclusion bodies (IBs). Since IBs contain ubiquitin and proteasome subunits, it was proposed that inhibition of proteasome activity might underlie pathogenesis of polyQ disorders. Recent in vitro enzymatic studies revealed the inability of eukaryotic proteasomes to digest expanded polyQ, thus suggesting that occasional failure of polyQ to exit the proteasome may interfere with its proteolytic function.

Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington's disease.

The primary mechanism responsible for Huntington's disease remains unknown. Postulated early pathogenic events include the following: impaired protein folding, altered protein degradation, mitochondrial dysfunction, and transcriptional dysregulation. Although related therapies can delay disease progression in mouse models, they target downstream and probably indirect effects of mutant-huntingtin expression.

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice.

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas.

Cooexpression of FTDP-17 tau and GSK-3beta in transgenic mice induce tau polymerization and neurodegeneration.

Here we have tested whether tau modification either by point mutation or by hyperphosphorylation can exert maximal pathogenic effects or if, on the contrary, both types of tau modifications can act synergistically to induce neuropathology. For this, we have combined transgenic mice overexpressing the enzyme GSK-3beta (Tet/GSK-3beta mice), with transgenic mice expressing Tau with a triple FTDP-17 mutation which develop prefibrillar tau-aggregates (VLW mice). Tet/GSK-3beta/VLW transgenic mice show tau hyperphosphorylation in hippocampal neurons.

Biochemical, ultrastructural, and reversibility studies on huntingtin filaments isolated from mouse and human brain.

Huntington's disease (HD) and eight additional inherited neurological disorders are caused by CAG triplet-repeat expansions leading to expanded polyglutamine-sequences in their respective proteins. These triplet-CAG repeat disorders have in common the formation of aberrant intraneuronal proteinaceous inclusions containing the expanded polyglutamine sequences. These aggregates have been postulated to contribute to pathogenesis caused by conformational toxicity, sequestration of other polyglutamine-containing proteins, or by interfering with certain enzymatic activities.

Neuronal induction of the immunoproteasome in Huntington's disease.

Huntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasome activity is impaired in vivo, we performed enzymatic assays for the three peptidase activities of the proteasome in brain extracts from the HD94 conditional mouse model of HD.