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...

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␤...

Alzheimer's disease is a chronic, age-related neurodegenerative disorder. Neurofibrillary tangles are among the pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles consist of abnormal protein fibers known as paired helical filaments. The accumulation of paired helical filaments is one of the most characteristic cellular changes in Alzheimer's disease. Tau protein, a

Rostro-caudal specificity of corticospinal tract (CST) projections from different areas of the cortex was assessed by retrograde labeling with fluorogold and retrograde transfection following retro-AAV/Cre injection into the spinal cord of tdT reporter mice. Injections at C5 led to retrograde labeling of neurons throughout forelimb area of the sensorimotor cortex and a region in the dorsolateral cortex near the barrel field (S2). Injections at L2 led to retrograde labeling of neurons in the posterior sensorimotor cortex (hindlimb area) but not the dorsolateral cortex. With injections of biotinylated dextran amine (BDA) into the main sensorimotor cortex (forelimb region), labeled axons terminated selectively at cervical levels. With BDA injections into caudal sensorimotor cortex (hindlimb region), labeled axons passed through cervical levels without sending collaterals into the gray matter and then elaborated terminal arbors at thoracic sacral levels. With BDA injections into the dorsolateral cortex near the barrel field, labeled axons terminated at high cervical levels. Axons from medial sensorimotor cortex terminated primarily in intermediate laminae and axons from lateral sensorimotor cortex terminated primarily in laminae III–V of the dorsal horn. One of the descending pathways seen in rats (the ventral CST) was not observed in most mice.