ChileAlzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid b-peptide (Ab). We report here molecular changes induced by Ab, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Ab fibrils, as an in vivo model of the disease. Results indicate that in both systems, Ab neurotoxicity resulted in the destabilization of endogenous levels of b-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3b promoted the survival of post-mitotic neurons against Ab neurotoxicity and recovered cytosolic b-catenin to control levels. Moreover, the neurotoxic effect of Ab fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Ab fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing b-catenin levels and improved the deficit in spatial learning induced by Ab. Our results are consistent with the idea that Ab-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.

Wnt signaling is essential for neuronal development and the maintenance of the developing nervous system. Recent studies indicated that Wnt signaling modulates long term potentiation in adult hippocampal slices. We report here that different Wnt ligands are present in hippocampal neurons of rat embryo and adult rat, including Wnt-4, -5a, -7a, and -11. Wnt-7a acts as a canonical Wnt ligand in rat hippocampal neurons, stimulates clustering of presynaptic proteins, and induces recycling and exocytosis of synaptic vesicles as studied by FM dyes. Wnt-3a has a moderate effect on recycling of synaptic vesicles, and no effect of Wnt-1 and Wnt-5a was detected. Electrophysiological analysis on adult rat hippocampal slices indicates that Wnt-7a, but not Wnt-5a, increases neurotransmitter release in CA3-CA1 synapses by decreasing paired pulse facilitation and increasing the miniature excitatory post-synaptic currents frequency. These results indicate that the presynaptic function of rat hippocampal neurons is modulated by the canonical Wnt signaling.Wnt signaling regulates crucial processes in all multicellular organisms, including cell proliferation, differentiation, migration, and morphogenesis. Since its discovery about 25 years ago, Wnt signaling has been extensively studied for its diverse roles in embryogenesis and cancer (1) and, more recently, in neural development and synaptic plasticity (2-5). Several studies suggest that Wnt factors play a role in the formation of neuronal connections, and other reports indicate a specific effect on synapse assembly; for example, in Drosophila embryos overexpression of the Wnt gene DWnt-3, encoding a protein localized in axonal processes, disrupted the formation of commissural tracts (6). Wnt-3 also regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons before the formation of sensory motoneuron synapses (7). In developing cerebellum cortex it has been found that conditioned medium from granule cells increases the diameter of mossy fiber axons and growth cone complexity, a result mimicked by 9). Wingless, the prototypical Drosophila Wnt, and its receptor are localized at the larval neuromuscular junction (10). Wingless is secreted by motoneurons and accumulates at both the pre-and postsynaptic terminals. The loss of Wingless leads to reduction in target-dependent synapse formation (10).The expression of Wnt ligands and proteins of the Wnt signaling machinery in the mature nervous system (11, 12) suggests that Wnt signaling plays a role in neuroprotection and synaptic plasticity in addition to its role in neurite patterning in the developing nervous system (3, 5, 13). Indeed, Wnt ligands can act locally to regulate changes in neuronal cell shape and pre-and postsynaptic terminals, which are thought to underlie changes in synaptic function and learning. Thus, Wnt ligands would appear to be particularly well suited as mediators of synaptic plasticity (5,14,15).In the present study we report that Wnt-7a, a canonical ligand that stimulates vesicle clusteri...

During the formation of synapses, specific regions of pre-and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre-and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and noncanonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95.During the formation of synapses, pre-and postsynaptic sides contain specific molecules that are involved in the regulation and plasticity of synaptic transmission (1-3). Although much is known about the molecular mechanisms of synaptic differentiation, major gaps remain in our understanding of the process, particularly with regard to the signals mediating the structuring of the postsynaptic apparatus of central mammalian synapses (2, 4). At excitatory synapses, the postsynaptic side is characterized by an electrodense thick matrix, called postsynaptic density (PSD).3 The PSD contains key molecules involved in the regulation of glutamate receptor targeting and trafficking (1, 5). There is considerable interest in elucidating the molecular mechanism that controls synaptic targeting and trafficking of these proteins in the postsynaptic region because of their essential role in synaptic plasticity (6). Moreover, in neurodegenerative pathologies, such as Alzheimer disease, it has been evidenced that the postsynaptic region, including several proteins of the PSD, is the primary target of the synaptotoxic effect of the amyloid ␤-peptide (7-9).Wnt signaling is essential for neuronal development and the maintenance of the nervous system (10 -12). Wnt regulates synapse formation; in fact, the pioneering work of Salinas and co-workers (12-15) established that Wnt-7a induces the clustering of presynaptic proteins in young primary cerebellar cultures. Also, Wnt ligands regulate neurogenesis of hippocampal stem cells in the adult rat (16), and Wnt-3a modulates long term potentiation in mouse hippocampal slices (17, 18).The expression of Wnt ligands and proteins of the Wnt signaling machinery in the matu...

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Language interference was elicited by electrical stimulation of the dominant basal temporal region in 8 out of 22 cases and in none of 7 cases with subdural electrodes implanted over the nondominant temporal lobe. Language interference was elicited by stimulation of electrodes placed over the fusiform gyrus 3-7 cm from the tip of the temporal lobe. Electrical stimulation of the basal temporal language area produced a global receptive and expressive aphasia with speech arrest at high stimulus intensities. Other higher cortical function, for example copying complex designs or memory of nonverbal information was intact, in spite of the total inability to process verbal information. At lower stimulus intensities partial aphasias with a predominant receptive component occurred. Surgical resection of the basal temporal language area produces no lasting language deficit.

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Oxidative stress is a key mechanism in amyloid ␤-peptide (A␤)-mediated neurotoxicity; therefore, the protective roles of 17␤-estradiol (E 2 ) and antioxidants (Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E 2 and Trolox attenuated the neurotoxicity mediated by A␤ and H 2 O 2 as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays, quantification of apoptotic cells, and morphological studies of the integrity of the neurite network. 2) Vitamin C failed to protect neurons from A␤ toxicity. 3) A␤-mediated endoperoxide production, reported to induce cell damage, was decreased in the presence of E 2 and Trolox. 4) Two key Wnt signaling components were affected by E 2 and Trolox; in fact, the enzyme glycogen synthase kinase 3␤ was inhibited by both E 2 and Trolox, and both compounds were able to stabilize cytoplasmic ␤-catenin. 5) E 2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E 2 , through the ␣-estrogen receptor, was able to prevent the excitotoxic A␤-induced rise in bulk-free Ca 2؉as an alternative pathway to increase cell viability. 6) Finally, the Wnt-7a ligand protected against cytoplasmic calcium disturbances induced by A␤ treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A␤ neurotoxicity. Alzheimer disease (AD)1 is a neurodegenerative disease characterized by neuronal cell death, dystrophic neurites, neurofibrillary tangles, and senile plaques (1). Senile plaques are composed by the amyloid ␤-peptide (A␤), a 40 -42-amino acid peptide that originates from the proteolytic cleavage of the amyloid precursor protein (2). There is also evidence relating the etiopathology of AD with oxidative stress induced by A␤ in the brain of AD patients (3-6). A␤ increases the production of intraneuronal reactive oxygen species (ROS) and stimulates hydrogen peroxide (H 2 O 2 ) levels through metal ion reduction (7,8). Free radicals peroxidize membrane lipids (9) and oxidize proteins (10). In vitro experiments also support the observation that the neurotoxic effect of A␤ is mediated by free radical mechanisms (5, 11, 12) and alteration of Ca 2ϩ homeostasis (13). Furthermore, several studies have reported neuroprotection by antioxidants against A␤-mediated cytotoxicity (14 -16). Also, 17␤-estradiol (E 2 ; estrogen) treatment apparently has beneficial effects on AD (17, 18). In addition, E 2 prevents A␤-induced cell death by activation of the ␣-ER (19) and preserves neuronal viability and function in cortical neurons exposed to glutamate toxicity (20). Also, there is evidence that E 2 prevents morphological neurodegenerative changes in hippocampal neurons caused by A␤ deposits (21).On the other hand, neurofibrillary tangles are intracellular aggregates of paired helical filaments produced by hyperphosphorylation of the microtubule-associated protein tau (23). It has been proposed that glycogen synthase kinase-3␤ (GSK-3␤...

GABA A receptors (GABA A -Rs) play a significant role in mediating fast synaptic inhibition and it is the main inhibitory receptor in the CNS. The role of Wnt signaling in coordinating synapse structure and function in the mature CNS is poorly understood. In previous studies we found that Wnt ligands can modulate excitatory synapses through remodeling both presynaptic and postsynaptic regions. In this current study we provide evidence for the effect of Wnt-5a on postsynaptic GABA A -Rs. We observed that Wnt-5a induces surface expression and maintenance of this receptor in the neuronal membrane. The evoked IPSC recordings in rat hippocampal slice indicate that Wnt-5a can regulates postsynaptically the hippocampal inhibitory synapses. We found also that Wnt-5a: (a) induces the insertion and clustering of GABA A -Rs in the membrane; (b) increases the amplitude of GABA-currents due exclusively to postsynaptic mechanisms; (c) does not affect the endocytic process, but increases the receptor recycling. Finally, all these effects on the GABA A -Rs are mediated by the activation of calcium/calmodulin-dependent kinase II (CaMKII). Therefore, we postulate that Wnt-5a, by activation of CaMKII, induces the recycling of functional GABA A -Rs on the mature hippocampal neurons.