A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease.

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies

Contribution of neural networks to Alzheimer disease's progression.

The neuropathology of Alzheimer disease is characterized by senile plaques, neurofibrillary tangles and cell death. These hallmarks develop according to the differential vulnerability of brain networks, senile plaques accumulating preferentially in the associative cortical areas and neurofibrillary tangles in the entorhinal cortex and the hippocampus. We suggest that the main aetiological hypotheses such as the beta-amyloid cascade hypothesis or its variant, the synaptic beta-amyloid hypothesis, will have to consider neural networks not just as targets of degenerative processes but also as contributors of the disease's progression and of its phenotype. Three domains of research are highlighted in this review. First, the cerebral reserve and the redundancy of the network's elements are related to brain vulnerability. Indeed, an enriched environment appears to increase the cerebral reserve as well as the threshold of disease's onset. Second, disease's progression and memory performance cannot be explained by synaptic or neuronal loss only, but also by the presence of compensatory mechanisms, such as synaptic scaling, at the microcircuit level. Third, some phenotypes of Alzheimer disease, such as hallucinations, appear to be related to progressive dysfunction of neural networks as a result, for instance, of a decreased signal to noise ratio, involving a diminished activity of the cholinergic system. Overall, converging results from studies of biological as well as artificial neural networks lead to the conclusion that changes in neural networks contribute strongly to Alzheimer disease's progression

Clusterin in neurological disorders: molecular perspectives and clinical relevance.

Firstly discovered in rete testis fluid, clusterin is a glycoprotein present in most of the other biological fluids. Several isoforms of clusterin are encoded from a single gene located on chromosome 8 in human species. Among the different isoforms, the secreted form of clusterin is expressed by a variety of tissues, including the nervous system under normal conditions. This form is presumed to play an anti-apoptotic role and seems to be a major determinant in cell survival and neuroplasticity after stroke. In animal models of this pathology, both neuronal and astroglial subpopulations express high levels of clusterin early after the ischemic damage. Recent lines of evidence point also to its possible involvement in neurodegenerative disorders. It is thought that in Alzheimer's disease the association between amyloidogenic peptides and clusterin contributes to limit Aβ species misfolding and facilitates their clearance from the extracellular space. Thus, intercellular and intracellular factors that modulate local clusterin expression in the nervous system may represent potent targets for neurodegenerative disease therapies. In this review we provide a critical overview of the most recent data on the involvement of clusterin in neurodegenerative diseases with special reference to their putative clinical relevance

A comparison of frailty of primary neurons, embryonic, and aging mouse cortical layers.

Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aβ peptides than deep layers V to VI in aging. Three models of layers were used to investigate this pattern of frailty. First, primary neurons from E14 and E17 embryonic murine cortices, corresponding respectively to future deep and superficial layers, were treated either with Aβ1-42, okadaic acid, or kainic acid. Second, whole E14 and E17 embryonic cortices, and third, in vitro separated deep and superficial layers of young and old C57BL/6J mice, were treated identically. We observed that E14 and E17 neurons in culture were prone to death after the Aβ and particularly the kainic acid treatment. This was also the case for the superficial layers of the aged cortex, but not for the embryonic, the young cortex, and the deep layers of the aged cortex. Thus, the aged superficial layers appeared to be preferentially vulnerable against Aβ and kainic acid. This pattern of vulnerability corresponds to enhanced accumulation of senile plaques in the superficial cortical layers with aging and Alzheimer's disease

Maladaptive exploratory behavior and neuropathology of the PS-1 P117L Alzheimer transgenic mice.

Patients with the early-onset Alzheimer's disease P117L mutation in the presenilin-1 gene (PS-1) present pathological hallmarks in the hippocampus, the frontal cortex and the basal ganglia. In the present work we determined by immunohistochemistry which brain regions were injured in the transgenic PS-1 P117L mice, in comparison to their littermates, the B6D2 mice. Furthermore, as these regions are involved in novelty detection, we investigated the behavior of these mice in tests for object and place novelty recognition. Limited numbers of senile plaques and neurofibrillary tangles were detected in aged PS-1 P117L mice in the CA1 only, indicating that the disease is restrained to an initial neuropathological stage. Western blots showed a change in PSD-95 expression (p=0.03), not in NR2A subunit, NR2B subunit and synaptophysin expressions in the frontal cortex, suggesting specific synaptic alterations. The behavioral tests repeatedly revealed, despite a non-significant preference for object or place novelty, maladaptive exploratory behavior of the PS-1 P117L mice in novel environmental conditions, not due to locomotor problems. These mice, unlike the B6D2 mice, were less inhibited to visit the center of the cages (p=0.01) and they continued to move excessively in the presence of a displaced object (p=0.021). Overall, the PS-1 P117L mice appear to be in an initial Alzheimer's disease-like neuropathological stage, and they showed a lack of reaction toward novel environmental conditions

Toward an Understanding of the Anion Effect in CpRu-Based Diels-Alder Catalysts via PGSE-NMR Measurements

The rate dependence of the [Ru(η5-C5H5)(BIPHOP-F)(acetone)][Y]-catalyzed Diels-Alder reaction of cyclopentadiene with methacrolein on the anion, Y, is shown to be due to selective ion pairing. Pulsed gradient spin-echo (PGSE) diffusion measurements on the model Cp and indenyl complexes [Ru(η5-C5H5)(CH2CH==CN)(BIPHOP-F)][Y], Y = BF4 and BArF, and [Ru(η5-C9H7)(CH2CH==CN)(BIPHOP-F)][Y], Y = BF4 and BArF, respectively, combined with 1H-19F HOESY NMR data can be used to understand how the ion pairing for the BF4 anion differs relative to that of the BArF anion. Solid-state structures for [Ru(η5-C5H5)(CH2CH==CN)(BIPHOP-F)][BF4] and [Ru(η5-C5H5)(CH2CH==CN)(BIPHOP-F)][BArF] are reported and support the NMR solution data. The model carbonyl complexes [Ru(η5-C5H5)(BIPHOP-F)(CO)][Y], 8 (Y = BF4, SbF6, and BArF) have been synthesized. The IR CO stretching frequencies for 8 showed little variation with anion, thereby proving that the anions do not affect the Lewis acidity of the salts