The AICD (amyloid precursor protein [APP] intracellular domain) and C31, the caspase-cleaved C-terminal fragment of APP, have been found in the brains of patients with Alzheimer's disease (AD). Here, we demonstrate for the first time that the C-terminal fragments of APP (AICD [C57, C59] and C31) exert neurotoxicity on differentiated PC 12 cells and rat primary cortical neurons by inducing the expression of glycogen synthase kinase 3beta, forming a ternary complex with Fe65 and CP2/LSF/LBP1 in the nucleus, whereas deletion mutants and a point mutant with Y682G of the YENPTY domain, a Fe65 binding domain, do not. Moreover, expression of APP770 and Swedish mutant form of APP increased the levels of C-terminal fragments of APP (APP-CTs) in neuronal cells and also induced the up-regulation of glycogen synthase kinase-3beta at both the mRNA and the protein levels. In addition, we show that CP2/LSF/LBP1 binding site (nt +0 to approximately +10) in human glycogen synthase kinase 3beta promoter region is essential for the induction of the gene transcription by APP-CTs. The neurotoxicities induced by APP-CTs (AICD and C31) were accompanied by an increase in the active form of glycogen synthase kinase-3beta, and by the induction of tau phosphorylation and a reduction in nuclear beta-catenin levels, and led to apoptosis.

Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)A␤42, but not oA␤40 or extracellular oA␤42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oA␤42-microinjected terminals, without affecting clathrincoated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD.Alzheimer's disease ͉ fluorescence microscopy ͉ presynaptic voltage clamp ͉ squid giant synapse ͉ ultrastructure C linically, Alzheimer's disease (AD) is manifested as a progressive deterioration of selective populations of neurons affecting particular cognitive domains, with initial symptoms indicating a decline in memory function. From a neuropathology perspective, AD has 2 major characteristics: (i) accumulations of extracellular aggregated peptide known as beta amyloid (A␤), which form the well-characterized senile plaques; and (ii) intracellular accumulation of an abnormally phosphorylated protein, tau, leading to the formation of neurofibrillary tangles. The early-onset familial form of AD (FAD) has a strong genetic association with the 42-aa species of the A␤ peptide (1-3). Also, autosomal dominant mutations in the genes for amyloid-␤ precursor protein (APP), presenilin 1 (PS1), and PS2 increase production of A␤42 and correlate significantly with the FAD syndrome. A␤ is a cleavage product of APP via the sequential action of 2 protease activities, the ␤ secretase and the ␥ secretase complex (4, 5); ␤ secretase cleaves APP at the N terminus, producing the membrane-bound moiety C99 and the secreted APPs␤ segment. Subsequently, C99 is cleaved by the ␥ secretase to generate the C terminus of A␤, resulting in a series A␤ peptides that are 38 to 43 aa in length. Under normal conditions, such events result in a higher proportion of A␤40 over A␤42 moieties. Under pathological conditions, such as in transgenic mice harboring human APP mutations, the production of A␤42 increases, followed by many pathophysiological features of AD, including amyloid plaques, dystrophic neurites, and synaptic dysfunction (5). Despite strong evidence that A␤42 is responsible for age-related memory decline, in humans, the extent of A␤ accumulation correlates poorly with memory abnormalities (6). Indeed, a specific challenge in addressing A␤ in AD concerned the role of specific aggregated pools of A␤ (e.g., extracellular, intracellular, membrane-associated, or insoluble) in the genesis of the pathology. Recently, AD symptoms were determined to be significantly co...

The role of P/Q-and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the Ca V 2.1 gene of the pore-forming α1A subunit for P/Q-type calcium channel, or the Ca V 3.1 gene of the pore-forming α1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the Ca V 2.1 −/− mice. In the Ca V 3.1 −/− mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or Ca V 2.1 −/− mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from Ca V 3.1 −/− mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both Ca V 2.1 −/− and Ca V 3.1 −/− mice. These results suggest that both α1A P/Q-and α1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics.

The incidence of amyloid plaques, composed mainly of bamyloid peptides (Ab), does not correlate well with the severity of neurodegeneration in patients with Alzheimer's disease (AD). The effects of Ab 42 on neurons or neural stem cells (NSCs) in terms of the aggregated form remain controversial. We prepared three forms of oligomeric, fibrillar, and monomeric Ab 42 peptides and investigated their effects on the proliferation and neural differentiation of adult NSCs, according to the degree of aggregation or concentration. A low micromolar concentration (1 lmol/L) of oligomeric Ab 42 increased the proliferation of adult NSCs remarkably in a neurosphere assay. It also enhanced the neuronal differentiation of adult NSCs and their ability to migrate. These results provide us with valuable information regarding the effects of Ab 42 on NSCs in the brains of patients with AD.