Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (4 > 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-␤ (A␤) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A␤ deposition and AD pathology, we compared APP V717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE ؊͞؊ ). A severe, plaque-associated neuritic dystrophy developed in APP V717F TG mice expressing mouse or human apoE. Though significant levels of A␤ deposition also occurred in APP V717F TG, apoE ؊͞؊ mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP V717F TG, apoE ؊͞؊ mice resulted in fibrillar A␤ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD. M ultiple lines of evidence suggest that the deposition of amyloid-␤ (A␤) peptides is an early pathogenic event inAlzheimer's disease (AD) that initiates a cascade of changes ultimately resulting in neuronal dysfunction, neurodegeneration, and eventual death (1). Conversion of A␤ from a soluble to an aggregated, insoluble form(s) with a ␤-sheet conformation may be central to its accumulation and possibly for its detrimental effects (2). The formation of a prominent neuritic dystrophy (e.g., neuritic plaques) is likely to account for a significant amount of neuronal and accompanying cognitive dysfunction in AD (3). Whether, how, and what form of A␤ causes this prominent neuritic dystrophy is unclear. Understanding the pathogenesis of neuritic degeneration and its relationship to A␤ deposition and aggregation may allow for development of preventive treatments.Transgenic (TG) mice that develop age-and regiondependent A␤ deposition have provided a major advance in AD research (4, 5). These mice allow for the study of both disease pathogenesis and potential treatment strategies targeted at A␤ deposition and fibrillogenesis as well as their consequences such as neuritic degeneration (4-7). One protein that may play a role in A␤ deposition and neuritic degeneration is apolipoprotein E (apoE). We observed a severe, plaque-associated neuritic dystrophy in APP V717F TG mice with most fibrillar A␤ deposits surrounded by both large and fine dystrophic neurites. Importantly, we found that apoE is required for the extensive, plaqueassociated neuritic degeneration. In APP V717F TG, apoE Ϫ͞Ϫ mice, extensive, nonfibrillar A␤ deposits developed; however, A␤-associated neuritic degeneration almost never was observed. Astrocyte-specific expression of human apoE3 and E4 in APP V717F TG, apoE Ϫ͞Ϫ mice ultimately restored fibrillar A␤ deposition by 15 months of age, with expression of apoE4 having a markedly greater effect on neuritic plaque formation than apoE3. Our data strongly suggest a critical and isoform-specific role of apoE in influenci...

Group II metabotropic glutamate receptors (mGluRs) comprise mGluR2 (mGlu2; encoded by GRM2) and mGluR3 (mGlu3; encoded by GRM3) and modulate glutamate neurotransmission and synaptic plasticity. Here we review the expression and function of mGluR3 and its involvement in schizophrenia. mGluR3 is expressed by glia and neurons in many brain regions and has a predominantly presynaptic distribution, consistent with its role as an inhibitory autoreceptor and heteroceptor. mGluR3 splice variants exist in human brain but are of unknown function. Differentiation of mGluR3 from mGluR2 has been problematic because of the lack of selective ligands and antibodies; the available data suggest particular roles for mGluR3 in long-term depression, in glial function and in neuroprotection. Some but not all studies find genetic association of GRM3 polymorphisms with psychosis, with the risk alleles also being associated with schizophrenia-related endophenotypes such as impaired cognition, cortical activation and glutamate markers. The dimeric form of mGluR3 may be reduced in the brain in schizophrenia. Finally, preclinical findings have made mGluR3 a putative therapeutic target, and now direct evidence for antipsychotic efficacy of a group II mGluR agonist has emerged from a randomised clinical trial in schizophrenia. Together these data implicate mGluR3 in aetiological, pathophysiological and pharmacotherapeutic aspects of the disorder.

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The ε4 allele of apolipoprotein E (ApoE) is an important genetic risk factor for Alzheimer's disease (AD). Increasing evidence suggests that this association may be linked to the ability of ApoE to interact with the amyloid‐β (Aβ) peptide and influence its concentration and structure. To determine the effect of ApoE on Aβ and other AD pathology in vivo, we used APPsw transgenic mice and ApoE knockout (−/−) mice to generate APPsw animals that carried two (ApoE +/+), one (ApoE +/−), or no copies (ApoE −/−) of the normal mouse ApoE gene. At 12 months of age, Aβ deposition was present in the cortex and hippocampus and was also prominent within leptomeningeal and cortical blood vessels of all APPsw ApoE +/+ mice. Importantly, although Aβ deposition still occurred in APPsw ApoE −/− mice, no fibrillar Aβ deposits were detected in the brain parenchyma or cerebrovasculature. There was also no neuritic degeneration associated with Aβ deposition in the absence of ApoE. These data demonstrate that ApoE facilitates the formation of both neuritic and cerebrovascular plaques, which are pathological hallmarks of AD and cerebral amyloid angiopathy. Ann Neurol 2000;47:739–747

The metabotropic glutamate receptor 3 (GRM3, mGluR3) is important in regulating synaptic glutamate. Here, we report the existence of three splice variants of GRM3 in human brain arising from exon skipping events. The transcripts are expressed in prefrontal cortex, hippocampus and cerebellum, and in B lymphoblasts. We found no evidence for alternative splicing of GRM2. The most abundant GRM3 variant lacks exon 4 (GRM3D4). In silico translation analysis of GRM3D4 predicts a truncated protein with a conserved extracellular ligand binding domain, absence of a seven-transmembrane domain, and a unique 96-amino acid C-terminus. When expressed in rat hippocampal neurons, GRM3D4 is translated into a 60 kDa protein. Immunostaining and cell fractionation data indicate that the truncated protein is primarily membraneassociated. An antibody developed against the GRM3D4 C-terminus detects a protein of approximately 60 kDa in human brain lysates and in B lymphoblasts, suggesting translation of GRM3D4 in vivo. The existence of the GRM3D4 isoform is relevant in the light of the reported association of non-coding single nucleotide polymorphisms (SNPs) in GRM3 with schizophrenia, and with the potential of GRM3 as a therapeutic target for several neuropsychiatric disorders.