Abeta Pathology Research Articles

Homozygosity for the K variant of BCHE gene increases the risk for development of neurofibrillary pathology but not amyloid deposits at young ages

The presence of the K variant of the butyrylcholinesterase gene (BCHE-K) has been associated with the severity of Alzheimer's disease (AD)-related neurofibrillary tangles (NFT) and amyloid beta-protein (Abeta). To examine the impact of BCHE-K on the development of initial NFT- and Abeta pathologies in young individuals below the age of 45 years a total of 124 cases (110 cases with NFT-only pathology, 14 cases with Abeta-only pathology) and 104 matched controls were genotyped for BCHE-K. Homozygosity for BCHE-K was highly overrepresented among NFT-only group (8.2%) compared with controls (1%, P = 0.02) or the Abeta-only group (0%). The prevalence of the K allele, however, was comparable among groups. These findings suggest that homozygosity, but not heterozygosity, for BCHE-K is a potential risk factor for the development of NFT pathology in young individuals implicating BCHE-K in the pathogenesis of early AD.

Enhanced accumulation of phosphorylated α‐synuclein in double transgenic mice expressing mutant β‐amyloid precursor protein and presenilin‐1

A recent report showed that the accumulation of alpha-synuclein (alpha-syn) was detected in the brains of one-third of Alzheimer's disease and Down syndrome patients. However, the relationship between amyloid-beta protein (Abeta) and alpha-syn remains unclear. We analyzed the relation between the mutation of presenilin-1 (PS-1) and the pathological features of beta-amyloidosis and alpha-synucleinopathy. We generated doubly transgenic mice overexpressing mutant beta-amyloid precursor protein (betaAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg betaAPP(+)/PS(+) mice at 5-23 months (young to old), 23 age-matched single Tg betaAPP(+)/PS(-) mice, and 11 non-Tg littermates. Immunohistochemical comparison was performed in these three groups by counting the area and the number of alpha-syn- or phosphorylated alpha-syn (palpha-syn)-positive dystrophic neurites per plaque (ASPDN, pASPDN). The acceleration of Abeta pathology was found with earlier onset and exaggerated numbers in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains, especially in pASPDN. The number and area of alpha-syn and palpha-syn, and the ratio of palpha-syn positive neurites were significantly higher in double Tg betaAPP(+)/PS(+) than in single Tg betaAPP(+)/PS(-) mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Abeta-induced alpha-synucleinopathy and further facilitated the phosphorylation of alpha-syn, suggesting a direct association between mutant PS-1 and phosphorylation of alpha-syn.

Genetically augmenting tau levels does not modulate the onset or progression of Aβ pathology in transgenic mice

The two hallmark pathologies of Alzheimer's disease (AD) are amyloid plaques, composed of the small amyloid-beta (Abeta) peptide, and neurofibrillary tangles, comprised aggregates of the microtubule binding protein, tau. The molecular linkage between these two lesions, however, remains unknown. Based on human and mouse studies, it is clear that the development of Abeta pathology can trigger tau pathology, either directly or indirectly. However, it remains to be established if the interaction between Abeta and tau is bidirectional and whether the modulation of tau will influence Abeta pathology. To address this question, we used the 3xTg-AD mouse model, which is characterized by the age-dependent buildup of both plaques and tangles. Here we show that genetically augmenting tau levels and hyperphosphorylation in the 3xTg-AD mice has no effect on the onset and progression of Abeta pathology. These data suggest that the link between Abeta and tau is predominantly if not exclusively unidirectional, which is consistent with the Abeta cascade hypothesis and may explain why tauopathy-only disorders are devoid of any Abeta pathology.

Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies?

The morphological differentiation of Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) is a matter of discussion. The objective of this study was to investigate the regional distribution of beta-amyloid (Abeta) plaques, alpha-synuclein (AS), and pathology in both disorders. The basal ganglia from 17 age-matched patients of PDD and DLB each were immunohistochemically examined with variable degrees of associated Alzheimer pathology using antibodies to Abeta, AS, and tau. DLB brains showed a significantly higher burden of (diffuse) amyloid plaques in the putamen and caudate nucleus and slightly more severe tau pathology than PDD brains despite similar neuritic Braak stages. Phases of Abeta development in DLB brains often, but inconsistently, correlated with both neuritic Braak stages and severity of striatal Abeta load, while these correlations were almost never seen in PDD cases with Alzheimer lesions. They also revealed a higher burden of AS-lesions (both Lewy neurites and Lewy bodies) than PDD cases that commonly had a paucity of all three types of lesion. The globus pallidus was virtually spared in both phenotypes. Differences in AS and Abeta pathologies and much less of tau lesions in the striatum support a morphologic distinction between PDD and DLB, which may be of pathophysiologic importance, but the causes of these differences are unclear.

Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.

Laminar distribution of beta-amyloid deposits in dementia with Lewy bodies and in Alzheimer's disease.

This study tested whether the laminar distribution of the beta-amyloid (Abeta) deposits in dementia with Lewy bodies (DLB) cases with significant Alzheimer's disease (AD) pathology (DLB/AD) was similar to "pure" AD. In DLB/AD, the maximum density of the diffuse and primitive deposits occurred either in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. A bimodal distribution of the classic Abeta deposits was also observed. Compared with AD, DLB/AD cases had fewer primitive deposits relative to the diffuse and classic deposits; the primitive deposits exhibited a bimodal distribution more frequently, and the diffuse deposits occurred more often in the upper laminae. These results suggest that Abeta pathology in DLB/AD may not simply represent the presence of associated AD.

Non‐fibrillar β‐amyloid abates spike‐timing‐dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors

Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.

Role of melatonin in Alzheimer-like neurodegeneration1

Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.

Effect of Acetylcholinesterase Inhibitors on AChE-Induced PrP106-126 Aggregation

Transmissible spongiform encephalopaties are caused by an extracellular surface protein, the scrapie prion protein (PrPsc), which is an aberrant form of normal and functional cellular PrP (PrPc). The pathological hallmarks of these diseases are the accumulation and deposition of PrPsc in the form of amyloid fibrils in the central nervous system (Tateishi et al., 1988), similar to amyloid-beta (Abeta) protein in Alzheimer's disease (AD). In some patients, Abeta and prion pathology can coexist (Hainfellner et al., 1998), and a common spatial pattern of protein deposition has been described (Armstrong et al., 2001). In addition, it is well-known that acetylcholinesterase (AChE) colocalizes with Abeta deposits of brains in AD patients and accelerates assembly of Abeta peptides through the peripheral site of the enzyme (Inestrosa et al., 1996). The aim of the present study was to analyze time course and concentration dependence of the AChE proaggregating effect on synthetic peptide-spanning residues 106-126 of human PrP (PrP106-126) and the reversion of this effect by different AChE inhibitors (AChEIs).

Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease: A LINK BETWEEN Aβ AND TAU PATHOLOGY

Accumulation of amyloid-beta (Abeta) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is thought to be a later downstream event. It is now well established that Abeta exists as monomers, oligomers, and fibrils. To study the temporal profile of Abeta oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation of plaques and tangles and cognitive impairments. We show that SDS-resistant Abeta oligomers accumulate in an age-dependent fashion, and we present evidence to show that oligomerization of Abeta appears to first occur intraneuronally. Finally, we show that a single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear Abeta pathology, and more importantly, tau pathology. Therefore, Abeta oligomers may play a role in the induction of tau pathology, making the interference of Abeta oligomerization a valid therapeutic target.

Post-mortem diagnosis of Alzheimer's disease

Alzheimer's disease is a slowly but continuously progressive degenerative disorder of the human central nervous system seen in approximately 15% of elderly people over the age of 65 years. Morphological hallmarks of this process are intra- and extracellular protein aggregates. The intraneuronal protein aggregates are primarily made up of abnormal phosphorylated tau-protein, which builds neurofibrillary tangles, neuropil threads and dystrophic neurites in neuritic plaques. The extracellular deposits consist of amyloid beta-protein (Abeta) aggregates showing the characteristics of amyloid fibrils. The evolution of neurofibrillary changes as well as Abeta-deposition in brain regions follows a distinct hierarchical sequence spanning many decades. Abeta deposition begins in the neocortex whereas neurofibrillary pathology starts in the allocortical nerve cells of the transentorhinal region. Both transformations continue to increase in severity and expand into further areas and regions. The hierarchical pattern allows an easily understandable staging of neurofibrillary and Abeta pathology which in turn reflects the clinical gravity of the disease. According to these stages a dementing disorder can be diagnostically attributed to Alzheimer's disease.

Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice

Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Abeta) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Abeta production has not been ruled out. We show that ibuprofen reduced Abeta brain levels in rats from exogenously infused Abeta in the absence of altered Abeta production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Abeta and inflammation-related molecules alpha1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor gamma) (PPARgamma) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1beta, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Abeta42 production, these observations suggest that ibuprofen reduction of Abeta pathology may not be mediated by altered Abeta42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1beta and its downstream target ACT).

ApoAI Deficiency Results in Marked Reductions in Plasma Cholesterol But No Alterations in Amyloid-β Pathology in a Mouse Model of Alzheimer's Disease-Like Cerebral Amyloidosis

Epidemiological studies suggest links between cholesterol metabolism and Alzheimer's disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Abeta pathology, we crossed the PDAPP transgenic mouse model of AD-like cerebral amyloidosis to apolipoprotein AI-null mice that have markedly reduced plasma cholesterol levels due to a virtual absence of high density lipoproteins, the primary lipoprotein in mice. Interestingly and in contrast to models using non-physiological high fat diets or cholesterol-lowering drugs to modify plasma cholesterol, we observed no differences in Abeta pathology in PDAPP mice of the various apoAI genotypes despite robust differences in plasma cholesterol levels between the groups. Absence of apoAI also resulted in reductions in brain but not cerebrospinal fluid cholesterol, but had no effect on brain apolipoprotein E levels. These and other data suggest that it is perhaps the level of brain apolipoprotein E, not cholesterol per se, that plays a primary role in brain Abeta metabolism.

Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice.

A growing body of evidence suggests a relationship between oxidative stress and beta-amyloid (Abeta) peptide accumulation, a hallmark in the pathogenesis of Alzheimer's disease (AD). However, a direct causal relationship between oxidative stress and Abeta pathology has not been established in vivo. Therefore, we crossed mice with a knockout of one allele of manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme, with Tg19959 mice, which overexpress a doubly mutated human beta-amyloid precursor protein (APP). Partial deficiency of MnSOD, which is well established to cause elevated oxidative stress, significantly increased brain Abeta levels and Abeta plaque burden in Tg19959 mice. These results indicate that oxidative stress can promote the pathogenesis of AD and further support the feasibility of antioxidant approaches for AD therapy.

Cholesterol modulates amyloid beta-peptide's membrane interactions.

The causal relationship between amyloid beta-peptide (Abeta) deposition and Alzheimer's disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Abeta pathology. Interestingly, cholesterol not only modulates Abeta synthesis, but also controls interactions between Abeta and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Abeta. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. In vitro and in vivo modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Abeta's disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Abeta. In this membrane region, cholesterol attenuates the membrane disordering effects of Abeta. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MbetaCD) treatment in vitro. On the other hand, statin treatment in vivo depletes a cholesterol pool in a membrane area, which is much less susceptible to Abeta's membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD.

Extracellular amyloid formation and associated pathology in neural grafts.

Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration.

Tau, where are we now?

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. Tau is primarily a neuronal protein, but it is becoming increasingly evident that tau is present in non-neuronal cells where it also plays important roles. Tau is the primary protein component of the filaments (both paired helical and straight filaments) found in Alzheimer's disease brain. Further there is an ever growing family of neurodegenerative diseases called "tauopathies" where tau pathology is the primary, defining characteristic with little or no Abeta pathology. These findings, along with the fact that mutations in the tau gene cause a group of diseases collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), clearly demonstrate that tau dysfunction results in neuronal dysfunction and death. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in Alzheimer's disease and in the tauopathies, both sporadic and familial.

Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology.

Metabolism of amyloid-beta peptide (Abeta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Since neprilysin is the only rate-limiting catabolic peptidase proven by reverse genetics to participate in Abeta metabolism in vivo, we performed detailed immunohistochemical analysis of neprilysin in mouse brain using neprilysin-deficient mice as a negative control. The aim was to assess, at both the cellular and subcellular levels, where Abeta undergoes neprilysin-dependent degradation in the brain and how neprilysin localization relates to Abeta pathology in amyloid precursor protein (APP)-transgenic mice. In hippocampus, neprilysin was present in the stratum pyramidale and stratum lacunosum-moleculare of the CA1-3 fields and the molecular layer of the dentate gyrus. Confocal double immunofluorescence analyses revealed the subcellular localization of neprilysin along axons and at synapses. This observation suggests that after synthesis in the soma, neprilysin, a type II membrane-associated protein, is axonally transported to the terminals, where Abeta degradation is likely to take place. Among various cell types, GABAergic and metabotropic glutamate 2/3 receptor-positive neurons but not catecholaminergic or cholinergic neurons, expressed neprilysin in hippocampus and neocortex, implying the presence of a cell type-specific mechanism that regulates neprilysin gene expression. As expected, Abeta deposition correlated inversely with neprilysin expression in TgCRND8 APP-transgenic mice. These observations not only support the notion that neprilysin functions as a major Abeta-degrading enzyme in the brain but also suggest that down-regulation of neprilysin activity, which may be caused by aging, is likely to elevate local concentrations of Abeta at and around neuronal synapses.