A case of conjunctival precursor T cell lymphoblastic lymphoma presenting with salmon colored conjunctival mass.

PURPOSE: T-Lymphoblastic lymphoma (T-LBL) is a rare malignant tumor originated from precursor T-lymphocytes that differentiate to T lymphocytes. We report a rare case of T-LBL presenting with conjunctival mass as the first sign. OBSERVATIONS: A 61-year-old man presented with a right salmon colored conjunctival mass. A biopsy was performed, and histopathologic examination showed dense lymphocyte proliferation in subepithelial substantia propria. Immunohistochemical staining was positive for CD7, CD10, and TdT; and negative for CD20. CD3 was negative in most parts PET-CT revealed abnormal uptake in the left cervix, anterior mediastinum, abdominal aortic lymph nodes, and multiple bones. From the above findings, stage IVA T-LBL was diagnosed. The patient received hyper CVAD therapy (cyclophosphamide + doxorubicin + vincristine + dexamethasone) and HD-MA therapy (high-dose methotrexate + cytarabine). Subsequently, an unrelated bone marrow transplant was performed. CONCLUSIONS AND IMPORTANCE: This case demonstrates the importance of considering rare lymphomas such as T-LBL in the differential diagnosis of ocular adnexal lymphoid neoplasms.

Vitreoretinal lymphoma occurring after systemic chemotherapy for primary conjunctival diffuse large B cell lymphoma: A case report.

INTRODUCTION: Ocular adnexal lymphoma and vitreoretinal lymphoma are rare forms of non-Hodgkin lymphoma. They are regarded as distinct disease entities due to the differences in molecular mechanism, management, and outcome. We present a rare case of conjunctival diffuse large B cell lymphoma (DLBCL) that developed to vitreoretinal lymphoma after systemic chemotherapy. PATIENT CONCERNS: A 60-year-old man presented with a left salmon-colored conjunctival mass. DIAGNOSIS: A biopsy was performed, and histopathologic examination showed DLBCL. Immunohistochemical staining was positive for CD20 with increased κ to λ light chain ratio. INTERVENTIONS: Bone marrow biopsy also revealed DLBCL. Gallium-67 scintigraphy showed abnormal uptake only in the left orbital lesion. Ann Arbor stage was estimated as IV. The patient underwent systemic combination chemotherapy and immunotherapy. OUTCOMES: Four months after the last course of chemotherapy, primary conjunctival DLBCL relapsed, manifesting vitreous opacity. Diagnostic vitrectomy confirmed a diagnosis of vitreoretinal lymphoma. LESSONS: Conjunctival DLBCL and vitreoretinal lymphoma are both DLBCL. After systemic chemotherapy for conjunctival DLBCL, the lymphoma may relapse in intraocular sites as secondary vitreoretinal lymphoma.

IL-17A-Mediated Immune-Inflammatory Periarticular Mass and Osteolysis From Impingement in Ceramic-On-Ceramic Total Hip Arthroplasty.

We present a rare case of symptomatic adverse local tissue reaction in a 54-year-old female patient who had undergone total hip arthroplasty with ceramic-on-ceramic bearing. Inflammatory periarticular mass and osteolysis developed in the absence of cobalt chrome alloy interfaces and a modular neck component. On the pathologic images, there was no clear evidence of gross metal staining of tissues, metal corrosion, and ceramic or metal wear particles. However, there were impingement scars on the titanium alloy femoral neck and acetabular cup associated with a high combined anteversion angle of 75° (stem: 40° and cup: 35°), suggesting titanium debris release in vivo. Immunohistochemical staining proved a predominant infiltration of CD4+ T cells and the corresponding IL-17A response to metal. We conclude that neck-rim impingement may lead to the development of adverse local tissue reaction (periarticular mass and osteolysis) due to a metal hypersensitivity with the production of proinflammatory cytokines (IL-17A) by CD4+ T cells even in ceramic-on-ceramic total hip arthroplasty.

Accumulation of cellular prion protein within ß-amyloid oligomer plaques in aged human brains.

Alzheimer's disease (AD) is the main cause of dementia, and ß-amyloid (Aß) is a central factor in the initiation and progression of the disease. Different forms of Aß have been identified as monomers, oligomers, and amyloid fibrils. Many proteins have been implicated as putative receptors of respective forms of Aß. Distinct forms of Aß oligomers are considered to be neurotoxic species that trigger the pathophysiology of AD. It was reported that cellular prion protein (PrPC ) is one of the most selective and high-affinity binding partners of Aß oligomers. The interaction of Aß oligomers with PrPC is important to synaptic dysfunction and loss. The binding of Aß oligomers to PrPC has mostly been studied with synthetic peptides, cell culture, and murine models of AD by biochemical and biological methods. However, the molecular mechanisms underlying the relationship between Aß oligomers and PrPC remain unclear, especially in the human brain. We immunohistochemically investigated the relationship between Aß oligomers and PrPC in human brain tissue with and without amyloid pathology. We histologically demonstrate that PrPC accumulates with aging in human brain tissue even prior to AD mainly within diffuse-type amyloid plaques, which are composed of more soluble Aß oligomers without stacked ß-sheet fibril structures. Our results suggest that PrPC accumulating plaques are associated with more soluble Aß oligomers, and appear even prior to AD. The investigation of PrPC accumulating plaques may provide new insights into AD.

The Diagnostic Utility of RAS Q61R Mutation-specific Immunohistochemistry in Epithelial-Myoepithelial Carcinoma.

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland cancer characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety and overlap of histologic features with other salivary gland tumors, there are broad differential diagnoses. The HRAS Q61R mutation has been reported to be frequent in and specific to EMC. We evaluated the usefulness of RAS Q61R mutant-specific immunohistochemical (IHC) staining for detecting this genetic alteration in EMC. We investigated 83 EMC cases and 66 cases of salivary gland tumors with an EMC-like component, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. Sanger sequencing was performed for HRAS, KRAS, and NRAS. The diffuse and membranous/cytoplasmic RAS Q61R IHC expression was observed in 65% of EMC cases, in which all cases harbored the HRAS Q61R mutation. IHC-positive cases were present only in de novo EMCs (54/76 cases, 71%) but not in EMCs ex pleomorphic adenoma. The immunoreactivity was almost always restricted to the myoepithelial cells. Conversely, all EMC cases lacking the HRAS Q61R mutation were negative on IHC. In addition, only 3% of EMC-like tumors showed the abovementioned immunopositivity. None of the cases examined carried KRAS or NRAS mutations. IHC for RAS Q61R is highly sensitive and specific for detecting the HRAS Q61R mutation in EMC. Since significant immunopositivity was almost exclusively identified in nearly two thirds of EMCs but seldom in the histologic mimics, the IHC of RAS Q61R is a useful tool for diagnosing EMC in general pathology laboratories.

A new method for diagnosing biochemical abnormalities of anterior cruciate ligament (ACL) in human knees: A Raman spectroscopic study.

Anterior cruciate ligament (ACL) plays an essential role in knee joint stability and kinematics. The microstructural irregularities such as cellular changes and disorganization of the extracellular matrix (ECM) alter the mechanical properties of the ligament, leading to a significant knee functional instability and progression of osteoarthritis (OA). So far, the identification of the local abnormality in ACL has routinely relied on invasive analytical techniques such as histology or biochemical assays. The non-invasive diagnosis using magnetic resonance imaging (MRI) is still limited to identifying the presence/absence of partial/complete ruptures and mucoid degeneration. In this study, laser micro-Raman spectroscopy with near-infrared excitation (785 nm) was applied to human ACL in order to establish optical algorithms for non-destructively diagnosing a degeneration state at molecular level. Raman spectra were obtained from 44 ex-vivo ACL specimens, and these were subsequently classified as an early (subclinical) and advanced (clinical) level of tissue degradation based on the histopathological scoring system. The significant differences in Raman peak intensities were found between the different degeneration groups, which were assigned to the vibrational modes of nucleic acids in cells, collagens, and phospholipids. Linear discriminant analysis (LDA) was performed to identify cut-off values for the distributions of Raman intensity and intensity ratios, which enable to best discriminate between the early and advanced degenerated tissues. Raman intensity algorithms derived from I1101/I1749, [I1002/I1516vs. I1101/I1749], and [I1002/I1749vs. I1101/I1749], yielded a maximum diagnostic sensitivity of 100%, specificity of 80%, and accuracy of 91% for discriminating the degeneration severity. STATEMENT OF SIGNIFICANCE: In this study, laser micro-Raman spectroscopy was applied to human anterior cruciate ligament (ACL) to establish optical algorithms for non-destructively diagnosing the tissue degeneration at molecular level. To our knowledge, this is the first report on Raman diagnosis for human ACL. Linear discriminant analysis (LDA) was performed to identify cut-off values for Raman intensity and intensity ratios, which enable to best discriminate between an early (subclinical) and advanced (clinical) level of ACL degeneration. The intensity ratios of I1101/I1749, [I1002/I1516vs. I1101/I1749], and [I1002/I1749vs. I1101/I1749] yielded a maximum diagnostic sensitivity of 100%, specificity of 80%, and accuracy of 91% for discriminating the ACL degeneration. The present findings might contribute to expanding clinical diagnostic possibilities for non-invasively identifying tissue degeneration.

Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-ß and Amyloid-ß Protein Precursor with Synapses.

Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-ß (Aß) have emerged as mediators of synapse dysfunction. Aß binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aß and the amyloid-ß protein precursor (AßPP) in AD remain poorly understood. In addition, the relative roles of Aß and AßPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aß/AßPP. We demonstrate that Aß binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aß42 accumulates in both glutamatergic and GABAergic AßPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AßPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AßPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aß/AßPP in AD can be important for the development of more effective new therapies for this major disease of aging.

Plaque formation and the intraneuronal accumulation of ß-amyloid in Alzheimer's disease.

Amyloid plaques and neurofibrillary tangles (NFTs) in the brain are the neuropathological hallmarks of Alzheimer's disease (AD). Amyloid plaques are composed of ß-amyloid peptides (Aß), while NFTs contain hyperphosphorylated tau proteins. Patients with familial AD who have mutations in the amyloid precursor protein (APP) gene have either increased production of Aß or generate more aggregation-prone forms of Aß. The findings of familial AD mutations in the APP gene suggest that Aß plays a central role in the pathophysiology of AD. Aß42, composed of 42 amino acid residues, aggregates readily and is considered to form amyloid plaque. However, the processes of plaque formation are still not well known. It is generally thought that Aß is secreted into the extracellular space and aggregates to form amyloid plaques. Aß as extracellular aggregates and amyloid plaques are thought to be toxic to the surrounding neurons. The intraneuronal accumulation of Aß has more recently been demonstrated and is reported to be involved in synaptic dysfunction, cognitive impairment, and the formation of amyloid plaques in AD. We herein provide an overview of the process of the intraneuronal accumulation of Aß and plaque formation, and discuss its implications for the pathology, early diagnosis, and therapy of AD.

Cytological features of mammary analogue secretory carcinoma of salivary gland: fine-needle aspiration of seven cases.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. There have been few case reports on the cytopathologic features of MASC to date. We examined the clinicopathological and cytological features of seven cases of MASC defined by RT-PCR analysis of the ETV6-NTRK3 fusion gene. The cases occurred in three men and four women aged between 39 and 68 years, with a mean of 51.6 years. In five of these seven cases, the tumor involved the parotid gland. Histologically, all cases displayed predominantly microcystic patterns, often a mixture of follicular and papillary-cystic structures. All tumors were immunoreactive for mammaglobin, S-100 protein, and vimentin. Available fine-needle aspiration cytology smears were cellular and exhibited many loosely cohesive syncytial clusters or isolated cells. Many histiocytes, some of which contained hemosiderin pigments, and variously shaped mucinous material were evident in the background or within the epithelial clusters. The majority of cases showed small to medium-sized follicular structures with secreted materials. Papillary clusters were occasionally found. Tumor cells exhibited small to medium-sized round to oval nuclei, with a smooth contour and indistinct or small nucleoli, and vacuolated cytoplasm. No tumor cells had obvious intracytoplasmic zymogen granules. It appeared that clusters of small to medium-sized follicular and papillary configurations consisting of bland tumor cells with vacuolated cytoplasm, but lack of intracytoplasmic zymogen granules, in a mucinous or hemosiderin-laden histiocyte-rich background, were a characteristic cytological feature highly suggestive of MASC.

Accumulation of intraneuronal ß-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses.

Pathologic aggregation of ß-amyloid (Aß) peptide and the axonal microtubule-associated protein tau protein are hallmarks of Alzheimer's disease (AD). Evidence supports that Aß peptide accumulation precedes microtubule-related pathology, although the link between Aß and tau remains unclear. We previously provided evidence for early co-localization of Aß42 peptides and hyperphosphorylated tau within postsynaptic terminals of CA1 dendrites in the hippocampus of AD transgenic mice. Here, we explore the relation between Aß peptide accumulation and the dendritic, microtubule-associated protein 2 (MAP2) in the well-characterized amyloid precursor protein Swedish mutant transgenic mouse (Tg2576). We provide evidence that localized intraneuronal accumulation of Aß42 peptides is spatially associated with reductions of MAP2 in dendrites and postsynaptic compartments of Tg2576 mice at early ages. Our data support that reduction in MAP2 begins at sites of Aß42 monomer and low molecular weight oligomer (M/LMW) peptide accumulation. Cumulative evidence suggests that accumulation of M/LMW Aß42 peptides occurs early, before high molecular weight oligomerization and plaque formation. Since synaptic alteration is the best pathologic correlate of cognitive dysfunction in AD, the spatial association of M/LMW Aß peptide accumulation with pathology of MAP2 within neuronal processes and synaptic compartments early in the disease process reinforces the importance of intraneuronal Aß accumulation in AD pathogenesis.

Immunohistochemical analysis of salivary gland tumors: application for surgical pathology practice.

Salivary gland tumors are relatively uncommon and there exists a considerable diagnostic difficulty owing to their diverse histological features in individual lesions and the presence of a number of types and variants, in addition to overlapping histological patterns similar to those observed in different tumor entities. The classification is complex, but is closely relevant to the prognostic and therapeutic aspects. Although hematoxylin-eosin staining is still the gold standard method used for the diagnosis, immunohistochemistry (IHC) can enhance the accuracy and be a helpful tool when in cases to investigate the subjects that cannot be assessed by histological examination, such as the cell nature and differentiation status, cell proliferation, and tumor protein expression. This review depicts on the practical diagnostic utility of IHC in salivary gland tumor pathology under the following issues: assessment of cell differentiation, focusing on neoplastic myoepithelial cells; discrimination of histologically mimic tumor groups; diagnosis of specific tumor types, e.g., pleomorphic adenoma, adenoid cystic carcinoma, and salivary duct carcinoma; and evaluation of malignancy and prognostic factors. IHC plays a limited, even though important, role in the diagnosis of salivary gland tumors, but is often useful to support the histological assessment. However, unfortunately few tumor type-specific markers are still currently available. For these reasons, IHC should be considered a method that can be used to assist the final diagnosis, and its results themselves do not directly indicate a definitive diagnosis.

An intrapelvic extraintestinal gastrointestinal stromal tumor of undetermined origin: diagnosis by prostate needle biopsy.

We herein report a case of intrapelvic gastrointestinal stromal tumor (GIST) of undetermined origin in a 48-year-old male who presented with dysuria. An enlarged tumor was detected on digital rectal examination. Imaging studies showed a solid and lobular homogenous tumor of 7.0 cm in diameter. The tumor was attached to the right dorsal aspect of the prostate with compression of the seminal vesicles and rectum. It was considered that the tumor had arisen from the prostate, although the patient's serum prostate-specific antigen level was low (0.436 ng/mL). The histological diagnosis by prostate needle biopsy was a spindle cell tumor. At cystoprostatectomy, the tumor was confirmed to be separated from the prostate by a fibrous band, and showed spindle cells with a fascicular growth pattern, but without necrotic areas. Mitotic figures were noted in 12 of 50 high-power fields. The tumor cells were immunoreactive for the KIT protein (CD117), CD34, Discovered on GIST-1 (DOG-1), and vimentin. In contrast, they were negative for desmin, α-smooth muscle actin, pancytokeratin (AE1/AE3), and S100 protein. The Ki-67 labeling index was 5%. The genetic analyses targeting the c-kit gene revealed a point mutation at codon 559 (GTT→GAT). The diagnosis of GIST was confirmed on the basis of the morphological features, immunoprofile, and results of the molecular analyses. Since extraintestinal GIST can resemble a prostatic tumor clinically, KIT (CD117) and DOG-1 should be considered for inclusion in the immunohistochemical panel for spindle cell tumors obtained by prostate needle biopsy.

[A case report of Kimura's disease causing visual dysfunction with remarkable eyelid swelling].

PURPOSE: We report a case of Kimura's disease involving the eyelids, presenting with bilateral eyelid swelling so severe that the eyelids could not be opened. CASE: A 37-year-old man presented with eyelid swelling and was unable to open both eyelids. He noted swelling and mass of bilateral eyelids since a year previously, and the masses enlarged gradually impairing eye-opening. Hard soft elastic tumors were palpated in both eyelids. Blood examination revealed marked peripheral blood eosinophilia and an increased serum IgE level. On T 1-weighted MR images, the tumors were observed as isointense masses compared to the extraocular muscles. On T 2-weighted images, the tumors showed hypointense signals while some parts were hyperintense compared to the extraocular muscles. On Gd-enhanced T 1-weighted images, the tumors demonstrated marked enhancement. The tumors in both eyelids were extirpated en bloc. Histopathology of the tumors demonstrated many lymphoid follicles and infiltration of large numbers of eosinophils and lymphocytes. Eosinophilic abscess and proliferation of blood capillaries were observed between the lymphoid follicles. These findings led to a diagnosis of Kimura's disease. PCR revealed clonal rearrangement of the T cell receptor gene. CONCLUSION: Kimura's disease may cause remarkable eyelid swelling and lead to visual dysfunction. Since recurrence of Kimura's disease is known to be associated with clonal rearrangement of T cell receptor genes, similar cases should be followed carefully for recurrence.

Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain.

Amyloid plaques, a well-known hallmark of Alzheimer's disease (AD), are formed by aggregated ß-amyloid (Aß). The cellular prion protein (PrPc) accumulates concomitantly with Aß in amyloid plaques. One type of amyloid plaque, classified as a neuritic plaque, is composed of an amyloid core and surrounding dystrophic neurites. PrPc immunoreactivity reminiscent of dystrophic neurites is observed in neuritic plaques. Proteinase K treatment prior to immunohistochemistry removes PrPc immunoreactivity from amyloid plaques, whereas Aß immunoreactivity is enhanced by this treatment. In the present study, we used a chemical pretreatment by a sarkosyl solution (0.1% sarkosyl, 75 mM NaOH, 2% NaCl), instead of proteinase K treatment, to evaluate PrPc accumulation within amyloid plaques. Since PrPc within amyloid plaques is removed by this chemical pretreatment, we can recognize that the PrP species deposits within amyloid plaques were PrPc. We could observe that PrPc accumulation in dystrophic neurites occurred differently compared with Aß or hyperphosphorylated tau aggregation in the AD brain. These results could support the hypothesis that PrPc accumulation in dystrophic neurites reflects a response to impairments in cellular degradation, endocytosis, or transport mechanisms associated with AD rather than a non-specific cross-reactivity between PrPc and aggregated Aß or tau.

Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease.

The aberrant accumulation of aggregated beta-amyloid peptides (Abeta) as plaques is a hallmark of Alzheimer's disease (AD) neuropathology and reduction of Abeta has become a leading direction of emerging experimental therapies for the disease. The mechanism(s) whereby Abeta is involved in the pathophysiology of the disease remain(s) poorly understood. Initially fibrils, and subsequently oligomers of extracellular Abeta have been viewed as the most important pathogenic form of Abeta in AD. More recently, the intraneuronal accumulation of Abeta has been described in the brain, although technical considerations and its relevance in AD have made this a controversial topic. Here, we review the emerging evidence linking intraneuronal Abeta accumulation to the development of synaptic pathology and plaques in AD, and discuss the implications of intraneuronal beta-amyloid for AD pathology, biology, diagnosis and therapy.

Co-occurrence of Alzheimer's disease ß-amyloid and τ pathologies at synapses.

Although beta-amyloid (Abeta) plaques and tau neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) neuropathology, loss of synapses is considered the best correlate of cognitive decline in AD, rather than plaques or tangles. How pathological Abeta and tau aggregation relate to each other and to alterations in synapses remains unclear. Since aberrant tau phosphorylation occurs in amyloid precursor protein (APP) Swedish mutant transgenic mice, and since neurofibrillary tangles develop in triple transgenic mice harboring mutations in APP, tau and presenilin 1, we utilized these well-characterized mouse models to explore the relation between Abeta and tau pathologies. We now report that pathological accumulation of Abeta and hyperphosphorylation of tau develop concomitantly within synaptic terminals.

Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations.

Immunotherapy against beta-amyloid peptide (Abeta) is a leading therapeutic direction for Alzheimer disease (AD). Experimental studies in transgenic mouse models of AD have demonstrated that Abeta immunization reduces Abeta plaque pathology and improves cognitive function. However, the biological mechanisms by which Abeta antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with Abeta antibodies decreases levels of intracellular Abeta. Antibody-mediated reduction in cellular Abeta appears to require that the antibody binds to the extracellular Abeta domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with Abeta antibodies protects against synaptic alterations that occur in APP mutant neurons.

Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system.

Increasing evidence links intraneuronal beta-amyloid (Abeta42) accumulation with the pathogenesis of Alzheimer's disease (AD). In Abeta precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Abeta42 occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that Abeta accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Abeta accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.

Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.

Synaptic dysfunction is increasingly viewed as an early manifestation of Alzheimer's disease (AD), but the cellular mechanism by which beta-amyloid (Abeta) may affect synapses remains unclear. Since cultured neurons derived from APP mutant transgenic mice secrete elevated levels of Abeta and parallel the subcellular Abeta accumulation seen in vivo, we asked whether alterations in synapses occur in this setting. We report that cultured Tg2576 APP mutant neurons have selective alterations in pre- and post-synaptic compartments compared to wild-type neurons. Post-synaptic compartments appear fewer in number and smaller, while active pre-synaptic compartments appear fewer in number and enlarged. Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density. In agreement, we observed early reductions in surface expression of glutamate receptor subunit GluR1 in APP mutant neurons. We provide evidence that Abeta is specifically involved in these alterations in synaptic biology, since alterations in PSD-95 and GluR1 are blocked by gamma-secretase inhibition, and since exogenous addition of synthetic Abeta to wild-type neurons parallels changes in synaptic PSD-95 and GluR1 observed in APP mutant neurons.