(2) and London mutation(s) (3) alter APP processing, causing increased production of the A␤ peptide of 42 amino acids (4), hypothesized to be pivotal in AD pathology (1, 5). Early onset familial AD caused by mutations in the presenilin genes supports this hypothesis, because they increase production of A␤ (42) peptide (6, 7) due to the gain of an unknown function (8). The extensive cell biological definition of the metabolic effects of the different mutations in APP in vitro requires matching analysis of their physiological impact in vivo. Transgenic mice with wild type and different mutant forms of APP have been generated and the original, most wanted end point, i.e. AD-like amyloid plaques in mouse brain, was obtained (9, 10), accompanied by cognitive deficits (11) and by hyperphosphorylation of protein tau (12). In other transgenic mouse strains overexpression of APP caused behavioral, synaptotrophic, and neurodegenerative effects, accelerated senescence, and premature death, in the absence of amyloid deposits (13-16). Intracellular expression of the A␤ peptide yielded mice with extensive neuronal loss but no amyloidosis (17). Overexpression of the C-terminal domain of APP caused neuronal degeneration (18), whereas in another model, pre-amyloid deposits, hippocampal cell loss, and cognitive deficits were documented (19).We have generated additional transgenic mouse strains, expressing human APP, either wild type or the London or Swedish clinical mutations, from the neuron-specific mouse thy-1 gene promoter. Their phenotype was analyzed by biochemical, histochemical, behavioral, electrophysiological, and pharmacological methods. Measurements of different APP metabolites in brain demonstrated that increased A␤(42) levels correlated with the formation of amyloid plaques in the brain of old APP/London transgenic mice. The plaques were extensively characterized immunohistochemically and displayed many aspects typically observed in the brain of AD patients. As opposed to plaques that developed only after at least 12 months of age, other deficits were observed from 3 months onwards and included cognitive impairment, decreased long term potentiation, differential glutamatergic responses, aggression, and neophobia, among others. These signs were largely independent of the actual isoform or mutant of APP that was expressed, were not correlated with a single APP metabolite, and are dissociated in time from plaque formation. These mice will be good models to study both early and late, neuropathological, and clinical aspects related to Alzheimer's disease. EXPERIMENTAL PROCEDURESGeneration of Transgenic Mice-cDNA coding for human wild type APP (695 isoform), the Swedish (K670N,M671L) mutant (770 isoform), and the London (V642I) mutant (695 isoform) were cloned in the pTSC vector in the mouse thy-1 gene (16). The purified, linearized minigenes were microinjected into prenuclear embryos from superovulated FVB/N females.Antibodies-Rabbit antisera B11/4 and B12/4, generated against a *

Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (a disintegrin and metalloproteinase) are the main candidates as physiologically relevant α-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP [V717I] increased the secretion of the neurotrophic soluble α-secretase-released N-terminal APP domain (APPsα), reduced the formation of Aβ peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD. 1456The

SUMMARY1. Single motor units were recorded with highly selective electrodes from intact tibialis anterior muscle in the adult man. A detailed parametric analysis was made of the discharge patterns during voluntary isometric contractions of different peak forces carried out at various rates of force development.2. During the smooth tracking of a ramp force, the different motor units recorded from a given muscle site were recruited in a consistent order, each unit becoming active when the muscle developed a certain level of force. The threshold of some of the units in such slow ramp contractions exceeded 8 kg. By contrast, in brisk ballistic contractions reaching a peak force of 12 kg in less than 0 15 sec, the same motor units discharged in a transient burst which largely preceded the muscle force production.3. In slow tracking ramp contractions, the instantaneous frequency of single motor units was initially rather low (5-15/sec) and it increased as the ramp force augmented. By contrast, in (strong) ballistic contractions, the same units discharged at an unusually high instantaneous frequency (60-120/sec) early in the burst and the firing frequency decreased thereafter. Such hitherto unknown pattern appears characteristic of ballistic contractions and it was not found in even fast tracking ramp contractions achieving 12 kg in only 0 4 sec. 4. The potentials of the different motor units activated are rather crowded at intervals of a few msec in the early burst of a strong ballistic contraction and observations on the rank activation of the different motor units do not provide reliable data for the analysis of the recruitment order of units in ballistic contractions.5. A new method is described for estimating ballistic force threshold of single motor units. When a large series of brisk ballistic contractions with peak forces ranging from 005 to 12 kg was carried out any given motor J. E. DESMEDT AND E. GODA UX unit only became active when the ballistic peak force exceeded a certain reproducible value. A detailed analysis of the recruitment order based on these ballistic force thresholds showed it to be virtually identical to the recruitment order of the same units in slow tracking ramp contractions (correlation = 0.95).6. Ballistic contractions are graded in force both by the recruitment of additional motor units in stronger contractions, and by an increase in their rate of firing. These gradation mechanisms are discussed.

In the brain of Alzheimer's disease (AD) patients, neurotoxic amyloid peptides accumulate and are deposited as senile plaques. A major therapeutic strategy aims to decrease production of amyloid peptides by inhibition of gamma-secretase. Presenilins are polytopic transmembrane proteins that are essential for gamma-secretase activity during development and in amyloid production. By loxP/Cre-recombinase-mediated deletion, we generated mice with postnatal, neuron-specific presenilin-1 (PS1) deficiency, denoted PS1(n-/-), that were viable and fertile, with normal brain morphology. In adult PS1(n-/-) mice, levels of endogenous brain amyloid peptides were strongly decreased, concomitant with accumulation of amyloid precursor protein (APP) C-terminal fragments. In the cross of APP[V717I]xPS1 (n-/-) double transgenic mice, the neuronal absence of PS1 effectively prevented amyloid pathology, even in mice that were 18 months old. This contrasted sharply with APP[V717I] single transgenic mice that all develop amyloid pathology at the age of 10-12 months. In APP[V717I]xPS1 (n-/-) mice, long-term potentiation (LTP) was practically rescued at the end of the 2 hr observation period, again contrasting sharply with the strongly impaired LTP in APP[V717I] mice. The findings demonstrate the critical involvement of amyloid peptides in defective LTP in APP transgenic mice. Although these data open perspectives for therapy of AD by gamma-secretase inhibition, the neuronal absence of PS1 failed to rescue the cognitive defect, assessed by the object recognition test, of the parent APP[V717I] transgenic mice. This points to potentially detrimental effects of accumulating APP C99 fragments and demands further study of the consequences of inhibition of gamma-secretase activity. In addition, our data highlight the complex functional relation of APP and PS1 to cognition and neuronal plasticity in adult and aging brain.

. Long-term plasticity of ipsilesional medial vestibular nucleus neurons after unilateral labyrinthectomy. J Neurophysiol 90: 184 -203, 2003. First published March 20, 2003 10.1152/jn.01140.2002. Unilateral labyrinthectomy results in oculomotor and postural disturbances that regress in a few days during vestibular compensation. The long-term (after 1 mo) consequences of unilateral labyrinthectomy were investigated by characterizing the static and dynamic membrane properties of the ipsilesional vestibular neurons recorded intracellularly in guinea pig brain stem slices. We compared the responses of type A and type B medial vestibular nucleus neurons identified in vitro to current steps and ramps and to sinusoidal currents of various frequencies. All ipsilesional vestibular neurons were depolarized by 6 -10 mV at rest compared with the cells recorded from control slices. Both their average membrane potential and firing threshold were more depolarized, which suggests that changes in active conductances compensated for the loss of excitatory afferents. The afterhyperpolarization and discharge regularity of type B but not type A neurons were increased. All ipsilesional vestibular cells became more sensitive to current injections over a large range of frequencies (0.2-30 Hz), but this increase in sensitivity was greater for type B than for type A neurons. This was associated with an increase of the peak frequency of linear response restricted to type B neurons, from 4 -6 to 12-14 Hz. Altogether, we show that long-term vestibular compensation involves major changes in the membrane properties of vestibular neurons on the deafferented side. Many of the static and dynamic membrane properties of type B neurons became more similar to those of type A neurons than in control slices, leading to an increase in the overall homogeneity of medial vestibular nucleus neurons.