Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of β-amyloid and α-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human β-amyloid peptides, α-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before α-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more α-synuclein-immunoreactive neuronal inclusions than α-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in α-synuclein singly tg mice. β-Amyloid peptides promoted aggregation of α-synuclein in a cell-free system and intraneuronal accumulation of α-synuclein in cell culture. β-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of α-synuclein and exacerbating α-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of β-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.
The secreted form (sAPP) of the Alzheimer amyloid beta/A4 protein precursor (APP) has been shown to be involved in the in vitro regulation of fibroblast growth and neurite extension from neuronal cells. The active site of sAPP responsible for these functions is within a small domain just C-terminal to the Kunitz-type protease inhibitor (KPI) insertion site. We report here that a 17-mer peptide, containing this active domain of sAPP, can induce cellular and behavioral changes when infused into rat brains. After 2 weeks of APP 17-mer peptide infusion, the animals were tested for reversal learning and memory retention and were sacrificed for morphological examination of brains. We found that administration of the APP 17-mer peptide resulted in an 18% increase in the number of presynaptic terminals in the frontoparietal cortex. At the behavioral level, 17-mer-infused animals with nonimpaired learning capability showed an increased memory retention that seemed to interfere with reversal learning performance. This APP 17-mer effect on memory retention was not observed in animals with impaired initial learning capacity. These results suggest that APP is involved in memory retention through its effect on synaptic structure.
Alzheimer's disease (AD) is characterized by both amyloid β (Aβ) plaque deposition and intracellular neurofibrillary tangles accompanied by progressive cognitive decline. Aged transgenic Tg2576 mice show both plaque and well characterized cognitive impairments in several behavioral tasks. We have shown that NPT001 (filamentous bacteriophage M13) directly and potently dissociates fibrillary Aβ present in plaques and that it mediates tau aggregate clearance, indicating that NPT001 has broad amyloid-targeted activity. A variant of NPT001, NPT002, is in preclinical development for AD. This study was conducted to evaluate whether NPT002-induced Aβ clearance in aged Tg2576 mice is accompanied by cognitive improvement in tasks of spatial (Y Maze) and episodic (Novel Object Recognition, NOR) memory. In the present study, we administered bilaterally a single intra-hippocampal 2μL dose of NPT002 (2x10 11, 2x10 10, or 2x10 9 phage particles/injection) or PBS to 18-19 month old male Tg2576 mice and age-matched littermates. Animals were tested in a Y-Maze and in an NOR paradigm 5 and 6 days post-treatment, respectively. Animals were sacrificed 7 days post-treatment. Paraformaldehyde-fixed brains were serially sectioned with a vibratome and analyzed for Aβ load in the hippocampus and surrounding cortical areas by thioflavin S and anti-amyloid antibody staining (82E1); for neuro-inflammation by antibody staining for Iba1 and GFAP. Aged Tg2576 mice showed a performance deficit in the Y-Maze compared to aged-matched wild-type littermates. A single treatment with NPT002 produced a statistically significant dose-dependent amelioration of cognitive deficits in the Y-Maze, with NPT002 restoring the transgenic animals' spontaneous alternation activity to levels equal to that of their wild-type littermates. NPT002 also produce a dose-dependent improvement in the NOR test. All three NPT002 doses statistically reduced the levels of Aβ in the hippocampus and in the adjacent cortical tissue as measured with Aβ antibody and Thioflavin S staining. NPT002 represents a novel approach for reducing Aβ plaque. In an aged transgenic mouse model of AD (Tg2576), NPT002 was shown to both safely reduce Aβ load and ameliorate cognitive performance within one week following a single intra-hippocampal treatment, thus illustrating its potential as a promising treatment strategy for Alzheimer's disease.
The primary purpose of the present series of experiments was to characterize the in vitro and in vivo pharmacology profile of 2-(4-methoxy-phenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride (AC-90179), a selective serotonin (5-HT2A) receptor inverse agonist, in comparison with the antipsychotics haloperidol and clozapine. The secondary purpose was to characterize the pharmacokinetic profile of AC-90179. Like all atypical antipsychotics, AC-90179 shows high potency as an inverse agonist and competitive antagonist at 5HT2A receptors. In addition, AC-90179 exhibits antagonism at 5HT2C receptors. In contrast, AC-90179 does not have significant potency for D2 and H1 receptors that have been implicated in the dose-limiting side effects of other antipsychotic drugs. The ability of AC-90179 to block 5-HT2A receptor signaling in vivo was demonstrated by its blockade of the rate-decreasing effects of the 5-HT2A agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride, under a fixed ratio schedule of reinforcement. Similar to clozapine and haloperidol, AC-90179 attenuated phencyclidine-induced hyperactivity. Although haloperidol impaired acquisition of a simple autoshaped response and induced cataleptic-like effects at behaviorally efficacious doses, AC-90179 and clozapine did not. Furthermore, unlike haloperidol and clozapine, AC-90179 did not decrease spontaneous locomotor behavior at efficacious doses. Limited oral bioavailability of AC-90179 likely reflects rapid metabolism rather than poor absorption. Taken together, a compound with a similar pharmacological profile as AC-90179 and with increased oral bioavailability may have potential for the treatment of psychosis.
AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) is a potent and selective muscarinic M-sub-1 receptor agonist. AC-260584 was evaluated in animal models: antipsychotic-like effects were tested by the ability to reduce amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing; catalepsy was assessed by measuring step-down latency; spatial memory was tested by using the Morris water maze. AC-260584 reduced amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing. In contrast to haloperidol, AC-260584 did not produce catalepsy. AC-260584 enhanced performance in the water maze during a probe test without a platform after 6 days of training, similar to the positive control tacrine. These data indicate that AC-260584 has a behavioral profile consistent with antipsychotic-like efficacy with the potential to improve cognitive performance and shows reduced liability for extrapyramidal symptoms.
