GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

As Alzheimer's disease pathogenesis is associated with the formation of insoluble aggregates of amyloid beta-peptide, approaches allowing the direct, noninvasive visualization of plaque growth in vivo would be beneficial for biomedical research. Here we describe the synthesis and characterization of the near-infrared fluorescence oxazine dye AOI987, which readily penetrates the intact blood-brain barrier and binds to amyloid plaques. Using near-infrared fluorescence imaging, we demonstrated specific interaction of AOI987 with amyloid plaques in APP23 transgenic mice in vivo, as confirmed by postmortem analysis of brain slices. Quantitative analysis revealed increasing fluorescence signal intensity with increasing plaque load of the animals, and significant binding of AOI987 was observed for APP23 transgenic mice aged 9 months and older. Thus, AOI987 is an attractive probe to noninvasively monitor disease progression in animal models of Alzheimer disease and to evaluate effects of potential Alzheimer disease drugs on the plaque load.

Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some of these mutations lead to an overproduction of tau isoforms with four microtubule-binding repeats. Here we have expressed the longest four-repeat human brain tau isoform in transgenic mice under the control of the murine Thy1 promoter. Transgenic mice aged 3 weeks to 25 months overexpressed human tau protein in nerve cells of brain and spinal cord. Numerous abnormal, tau-immunoreactive nerve cell bodies and dendrites were seen. In addition, large numbers of pathologically enlarged axons containing neurofilament- and tau-immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian degeneration and neurogenic muscle atrophy were observed. When motor function was tested, transgenic mice showed signs of muscle weakness. Taken together, these findings demonstrate that overexpression of human four-repeat tau leads to a central and peripheral axonopathy that results in nerve cell dysfunction and amyotrophy.

Human ␤-amyloid precursor protein (APP) transgenic mice are commonly used to test potential therapeutics for Alzheimer's disease. We have characterized the dynamics of ␤-amyloid (A␤) generation and deposition following ␥-secretase inhibition with compound LY-411575 Kinetic studies in preplaque mice distinguished a detergent-soluble A␤ pool in brain with rapid turnover (half-lives for A␤40 and A␤42 were 0.7 and 1.7 h) and a much more stable, less soluble pool. A␤ in cerebrospinal fluid (CSF) reflected the changes in the soluble brain A␤ pool, whereas plasma A␤ turned over more rapidly. In brain, APP C-terminal fragments (CTF) accumulated differentially. The half-lives for ␥-secretase degradation were estimated as 0.4 and 0.1 h for C99 and C83, respectively. Three different APP transgenic lines responded very similarly to ␥-secretase inhibition regardless of the familial Alzheimer's disease mutations in APP. Amyloid deposition started with A␤42, whereas A␤38 and A␤40 continued to turn over. Chronic ␥-secretase inhibition lowered amyloid plaque formation to a different degree in different brain regions of the same mice. The extent was inversely related to the initial amyloid load in the region analyzed. No evidence for plaque removal below baseline was obtained. ␥-Secretase inhibition led to a redistribution of intracellular A␤ and an elevation of CTFs in neuronal fibers. In CSF, A␤ showed a similar turnover as in preplaque animals demonstrating its suitability as marker of newly generated, soluble A␤ in plaque-bearing brain. This study supports the use of APP transgenic mice as translational models to characterize A␤-lowering therapeutics.Deposits of the A␤ peptide known as amyloid plaques are one of the defining pathological hallmarks of Alzheimer's disease, and aggregated A␤ species are considered to play a key role in disease pathogenesis (Hardy and Selkoe, 2002). Generation of A␤ from the membrane-bound ␤-amyloid precursor protein (APP) involves consecutive cleavage by the ␤-secretase BACE1 and the ␥-secretase complex (Wolfe, 2006). BACE catalyzes the cleavage at the N terminus of A␤, releasing a soluble form of APP (sAPP␤) and leaving a C-terminal fragment (C99) in the membrane. C99 is then processed by ␥-secretase, which possibly involves three successive cleavage steps (Zhao et al., 2005), finally yielding a set of A␤ peptides heterogeneous at the C terminus, with the most abundant ends at positions 40, 42, and 38. The other product of this cleavage is the APP intracellular domain thought to be a regulator of gene expression (Wolfe, 2006). The ␥-secretase is a complex composed of presenilins (PS1 or PS2), nicastrin, PEN-2 (presenilin enhancer-2), and anterior pharynx-defective protein 1 (APH-1). Considerable evidence suggests that the presenilins contain the active site of this intramembrane aspartyl protease (Wolfe, 2006). A large Article, publication date, and citation information can be found at

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