The γ-secretase complex plays a role in Alzheimer’s disease (AD) and cancer progression. The development of clinical useful inhibitors, however, is complicated by the role of the γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B γ-secretase in a murine Alzheimer’s disease model led to improvements of Alzheimer’s disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total γ-secretase activity in the human brain, thus specific targeting of Aph1B-containing γ-secretase complexes may be helpful in generating less toxic therapies for Alzheimer’s disease.

Regulated intramembrane proteolysis by ␥-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ␥-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-␥-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-␥-secretase. We demonstrate here that the Aph1B/C-␥-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC ؊/؊ mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects ␥-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.Alzheimer's ͉ knockout ͉ schizophrenia ͉ presenilin ͉ prepulse inhibition

Reasons for performing study: Different criteria have been described based on height reduction of the total myelographic contrast column and components of it as tests for compression of the spinal cord due to cervical stenotic myelopathy (CSM). Fifty percent height reduction of the dorsal myelographic column (DMC), <2 mm empiric height of the DMC and a 40% reduction of the ratio of stenosis calculated based on the height reduction of the entire dural diameter (DD) have been described as decision criteria for considering the test result positive. The reasons for selecting these decision criteria or their accuracies have rarely been reported. Objectives: To evaluate the accuracy of diagnostic criteria based on reduced height of the total myelographic column and components of it for diagnosing extradural spinal cord compression using different decision criteria, and make recommendations for consistent myelographic interpretation in horses suspected of having CSM. Methods: Four measurements were obtained by 2 readers in a retrospective sample population of 38 horses in which both cervical myelography and histopathological examination of the cervical spinal cord were performed. The prevalence of CSM in the sample was 50%. At intervertebral sites, the minimum heights of the DD and DMC were measured. At intravertebral sites, the maximum heights of the entire DD and DMC were obtained. Percent height reductions of the DMC and DD were determined as the ratio of minimum intervertebral height to maximum intravertebral height within the next cranial vertebra. Histological examination was used as the gold standard for determining the actual site of spinal cord compression. Sensitivity and specificity for the diagnostic criteria were estimated at each site in neutral and flexed neck positions using several different decision criteria. Conclusions: At C6-C7, in neutral or flexed neck position and using 20% reduction of DD, the test was highly sensitive and specific for CSM. At other sites, reduced height of the myelographic column generally was not accurate for diagnosing extradural spinal cord compression. Using 20% reduction of DD in neutral position at the mid-cervical sites, the test had only low sensitivity and high specificity. Flexion of the neck appeared to increase detection of spinal cord compression in the mid-cervical region, but also substantially increased the frequency of false-positive diagnoses. Potential relevance: By using the reported sensitivity and specificity estimates, readers may decide on a decision criterion for diagnosis of extradural spinal cord compression due to CSM. However, in planning a surgical correction, it is difficult to define a decision criterion that combines acceptable sensitivity and specificity, especially at the mid-cervical sites.

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A 3½-week-old Holstein heifer calf was presented to Cornell University Hospital for Animals (CUHA) with a 2-week history of intermittent fever, coughing, and decreased growth and a 1-week history of drooling and droopy ears. The calf had been treated with several antibiotics without marked improvement. On physical examination, the calf was depressed, underweight, bradycardic (heart rate 60 bpm) and febrile (103.4ЊF, 39.7ЊC). Clinical signs attributable to cranioventral pneumonia included bilateral mucopurulent nasal discharge, coughing, and abnormal bronchial tones. Intermittently, there were food particles in the nasal discharge, ptyalism, difficult prehension and mastication of food, and regurgitation of green material from both the nose and mouth. Neurologic examination revealed depression, bilateral facial nerve paresis (decreased lip, eyelid, and ear tone; absent palpebral or menace reflex), and bilateral vestibular disease (balance loss to either side, no head tilt, and loss of physiologic vestibular nystagmus). No abnormal nystagmus was observed, but the eyeballs did not show the physiologic vestibular eyedrop on head and neck extension. The gait was normal. The diagnosis of bilateral cranial nerve (CN) VII and VIII disease suggested bilateral otitis media/interna. Deep palpation of the base of the ears elicited a pain response and nonodorous otorrhea was present, indicating a component of otitis externa. Upper airway and esophageal endoscopy was consistent with dysphagia and disturbed esophageal motility and showed tracheal mucopus, nasopharyngeal collapse, dorsal displacement of the soft palate, and esophageal dilatation with few contractions. Thoracic radiography and transtracheal aspirate cytology (many degenerate neutrophils, few macrophages, large amounts of mucus, no bacteria) confirmed the presence of bronchopneumonia. The transtracheal aspirate yielded Arcanobacter pyogenes and Mycoplasma spp., but fluorescent antibody testing for common respiratory viruses was negative. CBC results were normal. Lumbosacral cerebrospinal fluid (CSF) had a slightly high nucleated cell count (9 nucleated cells/L, normal Ͻ5 cells/L; total protein concentration 17 mg/dL, normal Ͻ70 mg/dL). Lateral skull radiographs did not show abnormalities, but computed tomography (CT) imaging indicated that both tympanic bullae and the right petrous temporal bone were enlarged,

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A nine-year-old Quarter Horse gelding (horse 1) was presented to the Cornell University Hospital for Animals for evaluation of muscle atrophy of the cranial gluteal muscles of approximately 6 months duration. The muscle atrophy was insidious in onset and slowly progressive, with more rapid progression during the last 8 weeks. The horse showed an inability to climb hills and had a bilateral hindlimb lameness equally affecting both hind limbs. The horse gradually developed incontinence of feces and urine over the previous 4 weeks before presentation.Marked, bilaterally symmetric muscle atrophy of the gluteal, quadriceps, and caudal thigh muscles had occurred. Results of physical examination otherwise were normal and neurologic examination revealed a short-strided gait in both hind legs, normal cutaneous sensation including of sheath and penile skin, continuous paraphimosis, decreased anal tone, and absent tail and anal reflexes. Examination per rectum revealed fecal retention and a large atonic bladder with marked sediment collection on the ventral aspect. A neuroanatomic diagnosis of a spinal cord lesion at the level of L4 to S5 was made based on the neurologic examination and specifically the neurogenic atrophy starting with the quadriceps muscles.An initial lumbosacral cerebrospinal fluid (CSF) evaluation revealed no significant abnormalities. Results of a Western blot test for equine protozoal myelitis (EPM) on the CSF were negative. Results of a CBC and serum biochemical profile were within reference limits except for a mild hyperproteinemia (total protein, 7.9 g/dL; reference range, 5.7-7.7 g/dL) due to hyperglobulinemia (5.1 g/dL; reference range; 2.4-4.4 g/dL).Nuclear scintigraphy of the lumbar and gluteal region with technetium-labeled methylene diphosphonate a (MDP; 140 mCi) revealed a marked focal increased activity on the dorsal aspect of the caudal lumbar vertebrae near the lumbosacral articulation, indicating inflammation or remodeling of the vertebral bodies. Lateral radiographs of the lumbar vertebrae, taken under general anesthesia, showed an aggressive bone lesion along the dorsal aspect of L5 and L6, characterized by diffuse bone lysis and irregular new bone formation. After taking another CSF sample, a lumbar my-