A transmembrane aspartyl protease termed -site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid- precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid- (A) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to A amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and ␣-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of A in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1⌬E9 mice prevents both A deposition and age-associated cognitive abnormalities that occur in this model of A amyloidosis. Moreover, A deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1 Ϫ/Ϫ mice are prevented by coexpressing APPswe;PS1⌬E9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate A amyloidosis in AD.
-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid- precursor protein (APP) leading to the generation of amyloid- peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1 ؉/؊ mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1 ؊/؊ mice with impaired processing of NRG1. We demonstrate that BACE1 ؊/؊ mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1 ؊/؊ mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1 ؊/؊ mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.clozapine ͉ dizocilpine ͉ neuregulin ͉ prepulse inhibition ͉ spine density B ACE1 (-site APP-cleaving enzyme 1), is the rate-limiting enzyme that makes the initial cleavage of the amyloid- (A) precursor protein (APP) and, in concert with ␥-secretase, gives rise to the plaque-forming -amyloid peptides in Alzheimer's disease (AD) (1). Deletion of BACE1 prevents the formation of A in vitro and in vivo and the cognitive abnormalities in mouse models of A amyloidosis. These findings strongly support BACE1 as an attractive therapeutic target for AD (1-3). In addition to APP, a number of other putative substrates for BACE1 have been identified, suggesting that BACE1 has multiple physiological functions (2). For example, recent studies indicate that BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) (4, 5), a ligand for members of the ErbB family of receptor-tyrosine kinases. This signaling pathway have numerous roles in CNS development and functions, including synapse formation, plasticity, neuronal migration, myelination of central and peripheral axons, and the regulation of neurotransmitter expression and function (6, 7). In addition to these physiological functions, NRG1 is one of the first genes that has been linked to an increased risk of schizophrenia (8). The disease-associated single-nucleotide polymor...
Attentional functioning in mice was assessed in an analogue of the five-choice serial reaction time task in which the requirement was to detect brief visual stimuli presented across five spatial locations. Two hybrid strains of mice were assessed; F1 C57Bl/6xDBA/2 and C57Bl/6x129sv. Both strains acquired the task to high levels of performance with, in particular, no problems due to premature responding. At performance, systematic manipulation of the task parameters indicated a pattern of effects consistent with the task, taxing aspects of visuospatial attention. There were some differential effects of task manipulations at baseline across strain. However, the pattern of effects suggested these were likely to be the result of effects on factors other than attentional functioning per se, such as behavioural reactivity and inhibition. There was evidence in both strains of specific, centrally mediated effects of scopolamine on attentional functioning, with the C57Bl/6xDBA/2 hybrid showing greater sensitivity to the drug manipulation. Specific effects on discriminative accuracy were observed at doses of 0.02 and 0.2 mg/kg scopolamine. At the 2 mg/kg dose, large reductions in accuracy were associated with large effects on other measures, including omissions and response latencies, suggestive of nonspecific effects on task performance. These data indicate, for the first time, the utility of operant methods in assessing visuospatial attentional functioning in mice. They confirm the importance of cholinergic mechanisms in attentional processes across species, and suggest interactions between cholinergic mechanisms and genotype in the expression of attentional phenotypes.
Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ϳ5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150 Glued . Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150 Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.
Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS (ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2 Ϫ/Ϫ ) mice. Although ALS2 Ϫ/Ϫ mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2Ϫ/Ϫ mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2 Ϫ/Ϫ mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress.
-Amyloid precursor protein cleavage enzyme 1 (BACE1) has been identified as a major neuronal -secretase critical for the formation of -amyloid (A) peptide, which is thought responsible for the pathology of Alzheimer's disease (AD). Therefore, BACE1 is one of the key therapeutic targets that can prevent the progression of AD. Previous studies showed that knocking out the BACE1 gene prevents A formation, but results in behavioral deficits and specific synaptic dysfunctions at Schaffer collateral to CA1 synapses. However, BACE1 protein is most highly expressed at the mossy fiber projections in CA3. Here, we report that BACE1 knock-out mice display reduced presynaptic function, as measured by an increase in paired-pulse facilitation ratio. More dramatically, mossy fiber long-term potentiation (LTP), which is normally expressed via an increase in presynaptic release, was eliminated in the knock-outs. Although long-term depression was slightly larger in the BACE1 knock-outs, it could not be reversed. The specific deficit in mossy fiber LTP was upstream of cAMP signaling and could be "rescued" by transiently elevating extracellular Ca 2ϩ concentration. These results suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release, at mossy fiber synapses.
Loss-of-function mutations in the DJ-1 gene account for an autosomal recessive form of Parkinson's disease (PD). To investigate the physiological functions of DJ-1 in vivo, we generated DJ-1 knockout (DJ-1 -/-) mice. Younger (< 1year) DJ-1 -/-mice were hypoactive and had mild gait abnormalities. Older DJ-1 -/-, however, showed decreased bodyweight and grip strength, and more severe gait irregularities compared to wild-type littermates. The basal level of extracellular dopamine, evoked dopamine release and dopamine receptor D2 sensitivity appeared normal in the striatum of DJ-1 -/-mice, which was consistent with similar results between DJ-1 -/-and controls in behavioral paradigms specific for the dopaminergic system. An examination of spinal cord, nerve and muscle tissues failed to identify any pathological changes that were consistent with the noted motor deficits. Taken together, our findings suggest that loss of DJ-1 leads to progressive behavioral changes without significant alterations in nigrostriatal dopaminergic and spinal motor systems.
Although ␥-secretase is recognized as a therapeutic target for Alzheimer's disease, side effects associated with strong inhibition of this aspartyl protease raised serious concerns regarding this therapeutic strategy. However, it is not known whether moderate inhibition of this enzyme will allow dissociation of beneficial effects in the CNS from mechanism-based toxicities in the periphery. We tested this possibility by using a series of mice with genetic reduction of ␥-secretase (levels ranging from 25 to 64% of control mice). Here, we document that even 30% reduction of ␥-secretase can effectively ameliorate amyloid burden in the CNS. However, global reduction of this enzyme below a threshold level increased the risk of developing squamous cell carcinoma as well as abnormal proliferation of granulocytes in a ␥-secretase dosage-dependent manner. Importantly, we demonstrate that there exists a critical ␥-secretase level that reduces the risk of amyloidosis in the CNS and limits tumorigenesis in epithelia. Our findings suggest that moderate inhibition of ␥-secretase represents an attractive anti-amyloid therapy for Alzheimer's disease.
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