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.
Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid- (A), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of A-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state A levels, because both endogenous and transgene-derived A are increased in enriched animals. These results demonstrate that the generation of A in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.
BackgroundThe proteases (secretases) that cleave amyloid-β (Aβ) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Aβ production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis.Methods and FindingsWe have generated a transgenic mouse model that genetically mimics the arrest of Aβ production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Aβ deposits retain a considerable amyloid load, with little sign of active clearance.ConclusionThis study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Aβ production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.
Memory loss in Alzheimer’s disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.DOI: http://dx.doi.org/10.7554/eLife.23798.001
-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...
Recent studies suggest that some aspects of learning and memory may be altered by a midlife loss of estrogen, indicating a potential causal relationship between the deficiency of ovarian hormones and cognitive aging. In this study, the effects of estrogen withdrawal and replacement were tested in middle-aged Fischer-344 rats using different memory tasks. Estrogen withdrawal accelerated the rate of cognitive aging. A deficit first occurred 4 months after ovariectomy in working memory, which was tested in a delayed-nonmatching-to-position task, and progressed from long-delay to short-delay trials. Reference memory, which was tested in a place discrimination task and a split-stem T-maze, was not affected by aging or ovariectomy. The efficacy of estrogen in ameliorating the cognitive deficit in old rats depended on the type of treatment (acute vs chronic) and whether the aging-related decline in a particular cognitive process was aggravated by estrogen withdrawal. Chronic estrogen treatment (implants) was effective in improving working memory only when primed with repeated injections of estrogen, indicating that simulating the estrogen fluctuations of the estrous cycle may be more effective than the widely used mode of chronic pharmacological treatment. A challenge with scopolamine revealed that ovariectomy-induced cognitive deterioration coincided with a compromised cholinergic system. Importantly, the estrogen treatment that had restored effectively the cognitive abilities of old ovariectomized rats did not reduce their sensitivity to scopolamine. Taking into consideration that estrogen was highly effective against the amnestic action of scopolamine when tested in young-adult rats, these data emphasize that mechanisms of the protective effect of estrogen differ in young and old rats.
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