Familial British dementia: colocalization of furin and ABri amyloid

Familial British dementia (FBD) is an autosomal dominant condition caused by a point mutation in the stop codon of the BRI gene. This mutation extends the normal precursor protein (PP) of 266 amino acids to the next stop codon, which is at amino acid 277. Kim and colleagues demonstrated in vitro that furin can process both the normal protein BriPP and the extended protein ABriPP to produce C-terminal fragments of 23 and 34 amino acids. The abnormal C-terminal fragment, ABri, accumulates in FBD in the form of extracellular amyloid deposits. The objective of our study was to determine if furin is associated with ABri in FBD. Brain tissue of one case of FBD, four cases of Alzheimer's disease (AD) and two controls were studied by immunohistochemistry using antibodies against furin, beta-amyloid protein and ABri. In FBD, furin was found to be colocalized with ABri deposits and amyloid angiopathy in all areas examined. In contrast -amyloid deposits in AD were not immunostained by the furin antibody. In normal as well as pathological cases, clusters of neurons in the hippocampus and neocortex showed light to moderate furin immunostaining, while peptidergic neurons of the hypothalamus showed intense furin-immunostaining. These data suggest that furin may be involved in producing the pathological fragment of ABriPP in vivo and that inhibition of furin might be a method of treating this disorder.     

Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease

Introduction: Two different disease‐specific mutations in the BRI2 gene, situated on chromosome 13, have been identified as giving rise to familial British dementia (FBD) and familial Danish dementia (FDD). Each mutation results in extension of the open reading frame generating the disease‐specific precursor proteins which are cleaved by furin‐like proteolysis releasing the amyloidogenic C‐terminal peptides ABri and ADan in FBD and FDD, respectively. Material and methods: To understand the mechanism of the formation of amyloid lesions in FBD, we studied the origin of the precursor proteins and furin in the human brain. We used control brains, cases of sporadic Alzheimer's disease (AD), variant AD with cotton wool plaques and FBD to study BRI2 mRNA expression using in situ hybridization. Furin and BRI2 protein expression was investigated using Western blotting and immunohistochemistry. Results: BRI2 mRNA and BRI2 protein are widely expressed primarily by neurones and glia and are deposited in the amyloid lesions in FBD. They were, however, not expressed by cerebrovascular components. Furin expression showed a similar pattern except that it was also present in cerebrovascular smooth muscle cells. Conclusions: These findings suggest that neurones and glia and are a major source of BRI2 protein and that in FBD, the mutated precursor protein may undergo furin cleavage within neurones to produce the amyloid peptide ABri. The failure to demonstrate BRI2 in blood vessels under the conditions tested suggests that vascular amyloid peptide production does not contribute significantly to cerebral amyloid angiopathy (CAA) in FBD and FDD, lending indirect support to the drainage hypothesis of CAA.     

Familial British dementia (FBD): a cerebral amyloidosis with systemic amyloid deposition

Introduction:  FBD is an autosomal dominant disease with neuropathological similarities to Alzheimer's disease (AD) as it is characterized by amyloid angiopathy, parenchymal amyloid plaque deposition and neurofibrillary degeneration. FBD is associated with a stop codon mutation in the BRI2 gene encoding a type II transmembrane protein, BriPP. Mutation results in an extended precursor protein, ABriPP, from which a C-terminal 34 amino acid peptide (ABri) is generated by furin-like proteolytic cleavage and deposited as amyloid and preamyloid in the central nervous system. Despite the morphological parallels with AD the sequences of the amyloidogenic peptides, ABri in FBD and Aβ in AD, are completely different. We examined systemic tissues in FBD for ABri deposition.
Materials and methods:  Immunohistochemistry using an ABri-specific antibody, Ab338, counterstained with Thioflavin S and Ab338 immuno-electron microscopy identified ABri deposits and determined whether these were amyloid or preamyloid in nature.
Results:  Amyloid bearing blood vessels stained positively for ABri in myocardium, uterus, bladder, spleen, pancreas, lung and skeletal muscle. ABri was also identified in either amyloid or preamyloid conformation in the parenchyma of myocardium, adrenal, pancreas and skeletal muscle.
Conclusion:  This study demonstrates that FBD is the first described cerebral amyloidosis with neurofibrillary pathology and dementia to be accompanied by systemic amyloid deposition.     

A morphometric and immunohistochemical study of the vestibular nuclear complex in bovine spongiform encephalopathy

Summary A morphometric and immunohistochemical study of the vestibular nuclear complex was performed on five bovine spongiform encephalopathy (BSE) and five control cow brains. Neurons of the lateral and superior vestibular nuclei were counted at 500-m intervals in 10-m-thick sections, using an image analysis system comprosing a projection microscope and digitising pad linked to a computer. A bimodal distribution of neuron diameters was recognised in the brains of normal cattle. One population of neurons had a mean diameter of 30 m and the other had a mean diameter of 60 m. The vestibular nuclei from BSE cattle had an approximately 50% reduction in total numbers of neurons when compared with controls (P<0.01). Cattle which were clinically diseased longer had the fewest number of neurons preserved. Diminshed numbers of neurons were detected throughout the area studied and affected neurons of all diameters. Immunohistochemical staining for synaptophysin a protein present in synapses throughout the CNS, showed no significant reduction in axon terminals synapsing with vestibular neurons, including vacuolated neurons of BSE brains, when controls and BSE brains were compared. This suggests that de-afferentation of neurons is not the cause of neuronal loss. Prion protein was detected in the neuropil of the vestibular nuclear complex of BSE brains but not control brains. These studies show that previously unsuspected neuronal loss is a significant feature of BSE.     

Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated -synuclein (anti-PSer129). Phosphorylated -synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated -synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.     

Immunohistological study on brains of Alzheimer's disease using antibodies to fetal antigens,C-series gangliosides and microtubule-associated protein 5

Summary An immunohistological study of Alzheimer's brains was performed using antibodies to C-series gangliosides and microtubule-associated protein 5 (MAP5), and their staining patterns were compared with those of antibodies to tau and -amyloid precursor protein. Antibodies to C-series gangliosides and MAP5, both of which are known to preferentially expressed in the fetal brains, immunostained dystrophic neurites of senile plaques, neurofibrillary tangles and neuropil threads abundant in 3rd and 5th layers in the cerebral cortex, all of which are considered to be pathological hallmarks of Alzheimer's disease. The immunostaining patterns of these structures by antibodies to C-series gangliosides and MAP5 were similar to those by the antibody to tau. These three antibodies also immunostained some neurons in Alzheimer's brain, although their staining patterns were slightly different from one another; i.e., both diffuse and granular patterns were seen by the antibody to tau, but only granular pattern by the antibodies to C-series gangliosides and MAP5. These neurons immunostained by these three types of antibodies appeared to be the precursors of the classical neurofibrillary tangles, as positively stained neurons were not seen in the brains of non-demented cases. The presence of fetal antigens such as the C-series gangliosides and MAP5 in Alzheimer's brain may suggest that regeneration or sprouting of neurons is ongoing in association with the re-induction of gene expression characteristic for the brain in the early stage of development.     

Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene

We report here a case of diffuse Lewy body disease with the A53T mutation in the -synuclein gene. The proband presented at the age of 41 years with parkinsonism that was poorly responsive to levodopa. She subsequently developed cognitive impairment and moderate dementia, and died at the age of 50. Her father, paternal grandfather and uncle were all reported to have suffered from Parkinsons disease. Staining of tissue sections from the probands brain with hematoxylin-eosin and -synuclein antibodies showed small numbers of Lewy bodies in a few brain regions. This contrasted with large numbers of Lewy neurites and neuroaxonal spheroids in many brain regions. By electron microscopy, Lewy neurites consisted of abnormal filaments and dense granular material. Isolated filaments resembled those previously described in idiopathic Parkinsons disease and dementia with Lewy bodies. They were decorated by antibodies specific for the N and C termini of -synuclein, indicating the presence of the full-length protein. Nucleus accumbens and the lower layers in limbic areas of the cerebral cortex showed prominent vacuolation, with frequent clustering of microvacuoles around Lewy neurites. Nerve cell loss was most extensive in dorsal motor nucleus of the vagus nerve, substantia nigra and nucleus basalis of Meynert. Neurofibrillary tangles and senile plaques were not observed. However, in several brain regions, a few widely scattered tau-positive nerve cell bodies and neurites were present. By electron microscopy, Alzheimer-type paired helical and straight filaments were seen.     

Rosenthal fibers,eosinophilic inclusions,and anchorage densities with desmosome-like structures in astrocytes in Alzheimer's disease

Ultrastructural study of the cerebral cortex of nine brains of individuals with Alzheimer's disease (AD) revealed four types of pathological changes of astrocytes. Rosenthal fibers were found in three cases, eosinophilic inclusions in one, anchoraged densities with desmosome-like structures in two, and corpora amylacea in four. In two biopsies, Rosenthal fibers were seen in less than 5% of astrocytes, but in a third biopsy with numerous plaques, tangles, and severe neuronal loss, they were present in about 40% of astrocytes. In one case with severe AD pathology and numerous Rosenthal fibers, the cytoplasm of some astrocytes was occupied by inclusions composed of electron-dense granules 3–6 m in diameter or aggregates of inclusions greater than 12 m in diameter. Ultrastructurally, they were similar to eosinophilic inclusions observed in Aicardi syndrome and brain malformations. The presence of eosinophilic inclusions in the brain of elderly persons with Alzheimer's disease does not confirm the previous suggestion that this form of astrocyte pathology is typical for protoplasmic astrocytes and developmental brain malformations. Development anchorage densities associated with hemidesmosome-like structures, which reinforce astrocyte cell membranes facing the perivascular space, may reflect adaptation of astrocytes to the complex of changes that occurs in atrophic brain. Morphological changes in astrocytes in areas with numerous plaques and massive infiltration of intercellular space with -amyloid fibrils and remnants of neurons and ghost tangles suggest that astrocyte pathology is a late unspecific reaction to the cascade of changes induced by -amyloid deposition that causes neuronal degeneration and brain atrophy.Supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and a grant from the National Institutes of Health, National Institute of Aging No. P01-AGO-4220     

Distribution of neuronal growth-promoting factors and cytoskeletal proteins in altered neurites in Alzheimer's disease and non-demented elderly

In the present immunohistochemical study, we investigated the characteristics of altered neurites in the frontal cortex of 10 Alzheimer's disease (AD) brains and 15 age-matched non-demented control brains. In both AD and control cases, the altered neurites in coronas of the classical plaques (CP) were frequently immunostained by antibodies to growth-promoting factors, N and C termini of amyloid precursor protein (APP), GAP43, collagen IV, laminin and the integrin receptor VLA6. The altered neurites in CP coronas in AD but not in controls were also immunostained by antibodies against normally and abnormally phosphorylated tau. Immunolabeling for microtubule-associated protein 2 was not found in CP from either group. Extensive neuropil threads (NT) and many neurofibrillary tangles (NFT), immunostained with tau and Alz50 antibodies, were present in AD neocortex but not seen in control cases. NT and NFT could not be stained by antibodies to the N termini of APP, GAP43, collagen IV, laminin and VLA6. Our findings indicate that in AD cases altered neurites in CP are undergoing both an aberrant sprouting process and a degenerating process. These altered neurites are probably of axon origin. NT and NFT may represent destructive changes. The presence of amyloid plaques, but absence of tau-related cytoskeletal pathology, in non-demented cases suggests that /A4 peptide is necessary but not sufficient to induce neurofibrillary pathology.     

Changes in hippocampal GABABR1 subunit expression in Alzheimer’s patients: association with Braak staging

Alterations in the -aminobutyric acid (GABA) neurotransmitter and receptor systems may contribute to vulnerability of hippocampal pyramidal neurons in Alzheimers disease (AD). The present study examined the immunohistochemical localization and distribution of GABA_B receptor R1 protein (GBR1) in the hippocampus of 16 aged subjects with a range of neurofibrillary tangle (NFT) pathology as defined by Braak staging (I–VI). GBR1 immunoreactivity (IR) was localized to the soma and processes of hippocampal pyramidal cells and some non-pyramidal interneurons. In control subjects (Braak I/II), the intensity of neuronal GBR1 immunostaining differed among hippocampal fields, being most prominent in the CA4 and CA3/2 fields, moderate in the CA1 field, and very light in the dentate gyrus. AD cases with moderate NFT pathology (Braak III/IV) were characterized by increased GBR1-IR, particularly in the CA4 and CA3/2 fields. In the CA1 field of the majority of AD cases, the numbers of GBR1-IR neurons were significantly reduced, despite the presence of Nissl-labeled neurons in this region. These data indicate that GBR1 expression changes with the progression of NFT in AD hippocampus. At the onset of hippocampal pathology, increased or stable expression of GBR1 could contribute to neuronal resistance to the disease process. Advanced hippocampal pathology appears to be associated with decreased neuronal GBR1 staining in the CA1 region, which precedes neuronal cell death. Thus, changes in hippocampal GBR1 may reflect alterations in the balance between excitatory and inhibitory neurotransmitter systems, which likely contributes to dysfunction of hippocampal circuitry in AD.     

Neuronal uptake of plasma proteins in brain contusions

Summary Twenty-five cases of cerebral contusions of varions age were examined immunohistochemically for neuronal uptake of albumin and fibrinogen. The neurons in the damaged areas were heavily stained in all cases, even in those of only a few minutes' survival, and they remained positive for serum proteins until they disappeared from the lesions. In hematoxylin and eosinstained sections, neuronal changes were observed from the first minutes after the lesion but they were indistinguishable from the shrunken dark neurons that occur as artifacts in poorly fixed material. However, in contrast to the artificially changed cells, the truely damaged ones took up serum proteins. It is concluded that staining with antisera against serum proteins may serve as early markers for neuronal injury before reliable histological changes have developed.     

The effect of intraperitoneal injection of GABA or GHBA on monoamine histofluorescence in the rat brain

Summary Using the Falck-Hillarp histofluorescence method we studied the effect of-aminobutyric acid (GABA) or-hydroxybutyric acid (GHBA) on catecholaminergic (CA) and serotoninergic (5-HT) neurons in the rat brain. Both GABA as well as GHBA enhanced the CA fluorescence in noradrenergic (NA) terminals in the cerebellar cortex, which suggested that the NA content increased in these terminals.GHBA but not GABA also enhanced the fluorescence in dopaminergic (DA) terminals in the neostriatum and limbic structures. No significant changes of fluorescence were found in 5-HT neurons after both compounds.The results obtained suggest that, apart from the known GABA-DA interaction, there exists also a GABA-NA interaction in the cerebellar cortex.     

The nature and timing of excitotoxic neuronal necrosis in the cerebral cortex,hippocampus and thalamus due to flurothyl-induced status epilepticus

Summary Flurothyl-induced status epilepticus was studied by light and electron microscopy (LM, EM) to determine the time course and structural features of neuronal necrosis in the vulnerable brain regions in epilepsy. The cerebral cortex, hippocampus and thalamus were examined after closely spaced recovery periods of up to 1 week. The results showed that acidophilic neurons appeared simultaneously in neurons of the neocortex, hippocampus and thalamus, and that this occurred within 1 h following the end of the epilepsy. The corresponding features of acidophilic neurons by EM were mitochondrial flocculent densities and large discontinuities in cell and nuclear membranes. Dark neurons were ubiquitous during the epilepsy, but recovered almost universally. A few dark neuronal forms persisted and underwent cytorrhexis after 12-h recovery or longer. Axon-sparing dendritic lesions characteristic of excitotoxic neuronal death were found in the neuropil of the neocortex, and in both vulnerable CA1 and resistant CA3 neurons of the hippocampus. Other than acute edema, glial changes were absent. The findings support an excitotoxic mechanism in epilepsy-induced selective neuronal necrosis also in brain regions outside the hippocampus, and contrast with previous reports in ischemia and hypoglycemia in that neuronal necrosis occurs virtually immediately after an epileptic insult. No maturation of cell damage, as described in ischemia, was seen. Furthermore, even exceedingly dark neuronal forms and massive dendritic swelling must be considered sub-lethal or prelethal cellular changes. Lethal cellular changes include acidophilia by LM, cell membrane breaks, and mitochondrial flocculent densities by EM.Supported by the Alberta Hertage Foundation for Medical Research, the Swedish Society of Medicine, the Swedish Medical Research Council, the Magnus Bergvall Foundation, and the Research Funds of the Karolinska Institute.     

Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: similarities with Alzheimer's disease

Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.     

The presence of glutathione in primary neuronal and astroglial cultures from rat cerebral cortex and brain stem

Summary The concentration of the tripeptide glutathione (GSH) was measured in primary cultures of neurons and astroglial cells from rat cerebral cortex and brain stem. The concentration of GSH was found to be approximately 20 nmol/ mg protein in the neuronal culture from the cerebral cortex and ca. 40 nmol/ mg protein in the neuronal brain stem cultures. A GSH concentration of approximately 20 nmol/mg was observed in the astrocyte cultures from both brain regions. The possibility to increase the GSH concentration was tested by incubating the cultures in the presence of the GSH precursor -glutamylcysteine (-GC). In the cultured astrocytes -GC produced a dose-dependent increase in GSH. A similar increase was observed in the neuronal cultures, but this effect failed to reach statistical significance.     

Alterations in neuron morphology in mucopolysaccharidosis type I

Summary Morphological changes in neurons with inborn defects of the lysosomal hydrolase, -l-iduronidase, and with concomitant storage of glycosaminoglycans, were evaluated by Golgi staining in two animal models and compared to a similar study of a child with the same disease. Cortical pyramidal neurons in feline mucopolysaccharidosis type I often displayed axon hillock enlargements (meganeurites) and/or ectopic, secondary neuritic processes sprouting from this same region of the cell. The latter structures were prominent and often appeared longer than similar neurites reported in other neuronal storage discases. Although most meganeurites were aspiny, a few were observed which possessed spine-like processes or neurites. Other than these morphological changes in cortical pyramidal neurons, few other cell types displayed abnormalities demonstrable by Golgi impregnation. In the canine model of this disorder, abnormal Golgi-impregnated cortical neurons resembled more closely those seen in human mucopolysaccharidosis. That is, they possessed meganeurites which typically were aspiny in appearance. Ectopic neurite growth was not observed on any Golgi-impregnated neurons in the cases of canine or human mucopolysaccharidosis used in this study. The latter finding given the advanced ages of these cases, is consistent with the view that ectopic neuritogenesis seen in neuronal storage diseases may be subject to a developmental window, albeit one open well beyond the period of early postnatal maturation.Supported by the NIH (NS-18804, SUW; DK-25759, MEH; AM-32126, RMS)     

Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34) in the hippocampus of patients with Alzheimer disease and normal aged individuals

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer disease (AD). Previous studies have shown (i) that in vitro tau can be phosphorylated to an Alzheimer abnormally phosphorylated state-like protein by proline-directed protein kinases MAP kinase and p34^cdc2, and (ii) that the AD abnormally phosphorylated tau can be in vitro dephosphorylated by protein phosphatases PP-2B, PP-2A and PP-1 and not by PP-2C. However, to have a direct effect on the regulation of phosphorylation of tau, these enzymes should be present in the affected neurons. In the present study immunocytochemical localization of protein phosphatases PP-1, PP-2A, PP-2B and PTP, and protein kinases MAP kinase and p34^cdc2 were studied in the hippocampal formation of AD and as a control in non-demented elderly patients. All the protein phosphatases and protein kinases studied were localized to both granular and pyramidal neurons. In the pyramidal neurons, the enzymes staining was observed in neuronal soma and neurites. PTP-1B, PP-1 and PP-2A were also highly expressed in microglia. The topographical distributions of all the enzymes studied were similar, i.e. the intensity of immunostaining in hippocampus in end-plate (CA3 and CA4) > prosubiculum, subiculum > entorhinal cortex > dentate gyrus > CA2 > CA1. Furthermore, the expression of all the enzymes was also observed in the tangle-bearing neurons. The PP-2B staining of the tangle-bearing neurons was weaker than the unaffected neurons in the same tissue section field in AD cases.     

Markers of axonal injury in post mortem human brain

-Amyloid precursor protein (APP) can be detected immunocytochemically at sites of axonal injury in the brain, and has recently been found to be a useful marker for injured axons in patients who survived for only 3 h after head trauma. It is transported by last axonal transport and is thought to accumulate in detectable levels where the cytoskeleton breaks down. If this theory is correct, other substances should accumulate here in the same way, so we have used antibodies to other neuronal proteins to compare their efficacy as markers of axonal injury. SNAP-25, chromogranin A and cathepsin D also marked injured axons at all survival times studied (2.5h–2 weeks), although they were not as sensitive or specific as APP. Immunolabelling for the 68-kDa neurofilament subunit (NF68) was present in most uninjured axons, and allowed axonal swellings to be seen in some cases. Synaptophysin, GAP-43, ubiquitin or tau did not label any normal or injured axons in this study. We, therefore, suggest that APP should be the immunocytochemical marker of choice for the detection of injured axons. This study also showed that microwave antigen retrieval significantly enhances the immunoreactivity of SNAP-25, chromogranin A, synaptophysin, GAP-43, ubiquitin and tau, in addition to that of APP, in formalin-fixed, paraffin-embedded tissue, and reveals NF68 antigenicity where it was not previously detectable.Supported by the Home Office Policy Advisory Board for Forensic Pathology (UK)     

Memory deficits of British dementia knock-in mice are prevented by Aβ-precursor protein haploinsufficiency

Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD(KI) mice are a model of FBD that is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Aβ-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBD(KI) mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias.     

Immunohistochemical analysis of ubiquilin‐1 in the human hippocampus: Association with neurofibrillary tangle pathology

This post mortem immunohistochemical study examined the localization and distribution of ubiquilin‐1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer's disease (AD) dementia cases, and age‐matched cases without dementia. In Braak stages 0–I–II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of neurons in Cornu Ammonis (CA) fields and dentate gyrus granular neurons. In Braak stages III‐IV and V‐VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons; some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co‐localization most frequently in CA1 pyramidal neurons in Braak stage III‐IV and V‐VI cases. Further processing using the pan‐amyloid marker X‐34 revealed prominent UBL/X‐34 dual labeling of extracellular NFT confined to the CA1/subiculum in Braak stage V‐VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up‐regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3, CA4 and dentate gyrus, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end‐stage AD.