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PubMed1998

[Neuropathologic markers in degenerative dementias].

The number of neuropathological markers used for the diagnosis of degenerative dementias is rapidly increasing, and this is somewhat confusing: some lesions described a long time ago, such as ballooned cells, proved to be less specific than they were supposed to be; this is also the case for Lewy bodies, that have been recognised in a larger spectrum of disorders than thought a few years ago. On the contrary, for an increasing number of neuropathologists, Pick bodies are now mandatory for the diagnosis of Pick disease, and this contrasts with the prevalent opinions of the late sixties or seventies. There are a number of reasons for the changing significance of neuropathological markers. Three of them can be easily identified: 1) the burst of immunohistochemistry into neuropathology allowed an easier recognition, a better delineation and new pathophysiological approaches to old lesions, and a dramatic increase in the description of new markers, especially in glial cells; 2) in some conditions characterized by the number and distribution of some lesions rather than by their mere presence, such as aging and Alzheimer disease, a better neuroanatomical point of view permitted new insights into the concept of disease versus age-related changes; 3) more accurate clinicopathologic correlations showed clearly the need of grouping or lumping together some entities: for example, obvious relationship aroused between progressive supranuclear palsy and corticobasal degeneration; in contrast, distinguishing different disorders in the frontal lobe dementias grouped together into "Pick disease" was felt necessary. This review summarizes the main criteria for identification, and the presumed meaning of the chief markers indicating the presence of abnormally phosphorylated tau proteins, A beta peptides, and PrP proteins. Abnormally phosphorylated tau proteins can be stored in the neurons, and participate in the constitution of many lesions (neurofibrillary tangles, neuropil threads, abnormal processes of the crown of neuritic senile plaques, Pick bodies, granulo-vacuolar degeneration, argyrophilic grains). When seen in neuroglia, they are the chief constituents of various lesions that affect mainly astrocytes (abnormal tufts of fibres, astrocytic plaques, thorn-shaped astrocytes, spiny astrocytes) and also oligodendrocytes (oligodendroglial threads and coils, glial cytoplasmic inclusions). A beta peptides, in "preamyloid" and amyloid conformations, can be seen in the extracellular space (plaques, of the neuritic or non-neuritic varieties, diffuse, focal and granular deposits) and in the vascular walls (amyloid angiopathies). Some PrP deposits are also of the amyloid variety (kuru type, multicentric or florid plaques), but immunohistochemistry, far more sensitive than conventional studies, revealed a number of other lesions (perivacuolar, neuronal, "synaptic" deposits...). Numerous markers are easily detected by ubiquitin immunohistochemistry. Lewy bodies, Pick bodies, neurofibrillary tangles had already be identified by other methods. In contrast, some ubiquitin-positive inclusions are shown, by this technique only, in amyotrophic lateral sclerosis and other conditions which were thus related to this disease. Finally, this review deals with two classic markers, ballooned cells ("Pick cells") and spongiosis seen in disorders due to non conventional agents or prions (spongiform encephalopathies).

Biomarkers↗
PubMed1991

Sequestration of tau by granulovacuolar degeneration in Alzheimer's disease.

Antibodies directed against three regions of tau have been used in a histologic study of granulovacuolar degeneration (GVD) in Alzheimer's disease (AD). Granulovascular degeneration complexes, consisting of a dense granule in a less-dense vacuole, were found in hippocampal pyramidal neurons in all patients studied. Anti-tau antibodies directed against the N-and C-termini, and the repeat region of tau, were found to immunolabel the granule of the GVD complex. Intracellular neurofibrillary tangles also were labeled by these antibodies. In particular, MAb6.423, which recognizes tau protein sequestered in paired helical filaments (PHF) in AD, but not the normal tau proteins so far described in human brain, labeled GVD granules. Contrarily, a generic tau marker (MAb7.51), which immunolabels all known isoforms of isolated and expressed tau protein, including PHF-tau, did not label the GVD granule. These findings demonstrate that the entire tau molecule is sequestered within the GVD granule, and that the tau protein found in GVD complexes is antigenically related to that found in PHFs. There is, however, a difference in the way in which the repeat region of tau is incorporated into the two structures, making the MAb7.51 epitope unavailable in the GVD complex. These findings suggest that the formation of GVD complexes in hippocampal pyramidal neurons vulnerable to neurofibrillary degeneration may represent an alternative pathway for dealing with an aberrant molecular complex, which contributes to the formation of GVD granules and neurofibrillary tangles in AD.

Adult↗
PubMed1997

Transglutaminase activity is increased in Alzheimer's disease brain.

Transglutaminase is a calcium-activated enzyme that crosslinks substrate proteins into insoluble, often filamentous aggregates resistant to proteases. Because the neurofibrillary tangles in Alzheimer's disease have similar characteristics, and because tau protein, the major component of these tangles is an excellent substrate of transglutaminase in vitro, transglutaminase activity and levels were measured in control and Alzheimer's disease brain. Frozen prefrontal cortex and cerebellum samples from Alzheimer's disease and control cases matched for age and postmortem interval were used in the analyses. Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.

Aged↗
PubMed2002

[Parkinson syndrome and cognitive disorders].

The cognitive (executive) ability of patients with Parkinson's-disease (PD) deteriorates gradually during the progression of the disease. Fluency of speech, word finding, working memory, ability to plan the future and flexibility decline. Cognitive disturbance was found to be proportional with the speech, posture, gait and balance problems and can not be influenced by L-dopa substitution. Apart the dorsal and ventral mesolimbic dopaminergic systems the coerulo-cortical noradrenergic, serotoninergic and cholinergic systems are also impaired in PD. Subcortical dementia in PD can also be explained by the functional disability of dorsolateral and anterior cingular circuits. Attention deficit can be explained by the dopamine depletion of cingular cortex. Cortical Lewy bodies, neurofibrillary tangles, neurit plaques and additional vascular pathology should also play a role in cognitive impairment of PD. In several systemic degenerative diseases associating with Parkinson's syndrome (PS) i.e. progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) dementia can be detected with various severity, therefore the question arises concerning the correlation between cognitive disability and PS. Parkinson syndrome can also develop in frontotemporal dementias (FTD), Alzheimer's disease and cortical Lewy body disease (CLBD) but no correlation exists between motor disability and severity of dementia. In CLBD dementia can be the initial symptom in 18% of cases but PS can also preceeds the dementia. In PSP profound depletion of other monoaminergic neurotransmitter system was also reported. In FTDs associated with PS degeneration of substantia nigra, locus coeruleus and basal nucleus of Meynert has been reported with increased number of neurofibrillary tangles. In patients with vascular PS (VP) there is generally no tremor and rigidity, but pseudobulbar palsy, dementia, gate disturbance, incontinency appears; L-dopa treatment is generally ineffective. In VP no cellular loss can be found within the substantia nigra, but leukoaraiosis, lacunae in the white matter and basal ganglia are commonly demonstrated.

Brain↗
PubMedDate not supplied

Immunotherapy for Alzheimer's disease and other dementias.

OBJECTIVE: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RESULTS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. CONCLUSION: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.

Journal Article↗
PubMed2005

Immunotherapy for Alzheimer's disease and other dementias.

PURPOSE OF REVIEW: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RECENT FINDINGS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. SUMMARY: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.

Alzheimer Disease↗
PubMed2004

Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains.

In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.

Adult↗
PubMed1997

Reactivating kinase/p38 phosphorylates tau protein in vitro.

Neurofibrillary tangles, one of the major pathological hallmarks of Alzheimer-diseased brains, consist primarily of aggregated paired helical filaments (PHFs) of hyperphosphorylated tau protein. Tau from normal brain and especially from foetal brain is also phosphorylated on some of the sites phosphorylated in PHFs, mainly at serines or threonines followed by prolines. A number of protein kinases can phosphorylate tau in vitro; those that require or accept prolines include GSK3 and members of the mitogen-activated protein (MAP) kinase family, ERK1, ERK2, and SAP kinase-beta/JNK. In this report, we show that another member of the MAP kinase family, the stress-activated kinase p38/RK, can phosphorylate tau in vitro. Western blots with phosphorylation-sensitive antibodies showed that p38, like ERK2 and SAP kinase-beta/JNK, phosphorylated tau at sites found phosphorylated physiologically (Thr181, Ser202, Thr205, and Ser396) and also at Ser422, which is phosphorylated in neurofibrillary tangles but not in normal adult or foetal brain. These findings support the possibility that cellular stress might contribute to tau hyperphosphorylation during the formation of PHFs, and hence, to the development of tau pathology.

Alzheimer Disease↗
PubMed1997

Carboxyl-terminal fragments of beta-amyloid precursor protein bind to microtubules and the associated protein tau.

Alzheimer's disease is a neurodegenerative disorder characterized by protein depositions in intracellular and extracellular spaces in the brain. The intraneuronal deposits are formed by neurofibrillary tangles composed mainly of abnormally phosphorylated tau, a microtubule-associated protein, whereas the major constituent of the amyloid deposited extracellularly in the brain parenchyma and vessel walls is amyloid beta-protein (A beta). The proteolytic processing of the beta-amyloid precursor protein (beta PP) results in the generation of a complex set of carboxyl-terminal peptides that contain A beta. In this study, we have used fusion proteins containing carboxyl-terminal fragments of beta PP to investigate the association of beta PP with cellular components. We demonstrate that specific domains within the carboxyl end of beta PP contain binding sites for cytoskeletal components; one, within residues 1 to 28 of A beta, binds directly to tubulin, and the second one, within sequences carboxyl-terminal to A beta, binds tau and tubulin. We propose that the two neuropathological hallmarks of Alzheimer's disease, A beta deposition and neurofibrillary tangles, represent the residual of a disrupted beta PP-tubulin-tau complex.

Amyloid beta-Protein Precursor↗
PubMed2006

Alzheimer's disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits.

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve.

Alzheimer Disease↗
PubMed1991

Transplants of mouse trisomy 16 hippocampus provide a model of Alzheimer's disease neuropathology.

Alzheimer's disease, which is characterized by amyloid plaques and neurofibrillary tangles, may be attributed to the abnormal expression of gene(s) located on human chromosome 21. Genetic linkage studies have narrowed the region of candidate genes to 21q11.2-21q22 of the long arm of this chromosome. Several single copy sequences within this region, including the amyloid precursor protein (APP), have been mapped to mouse chromosome 16. Reliable strategies exist for breeding Trisomy 16 mice. However, the consequences of developmental overexpression of genes on chromosome 16 have not been previously investigated, because of the lethal effects of this aneuploidy during gestation. In the present report, we employ neural transplantation to study long-term survival and pathogenesis in Trisomy 16 central nervous system tissues. Immunocytochemical staining with antiserum raised against the synthetic APP, beta-A4 and alpha 1-antichymotrypsin revealed numerous densely stained cells within hippocampal grafts of Trisomy 16 mice. Similarly, a population of grafted cells were positively stained following incubation with an antiserum raised against components of the pathological neurofibrillary tangle and with the monoclonal antibodies Tau 6.423 and ubiquitin.

Alzheimer Disease↗
PubMed1988

Differential modification of muscarinic cholinergic receptors in the hippocampus of patients with Alzheimer's disease: an autoradiographic study.

We have used quantitative light microscopic autoradiographic techniques to analyze changes in muscarinic cholinergic receptors in the hippocampus in Alzheimer type dementia (ATD). The density and distribution of muscarinic cholinergic receptors has been correlated with the density of neurons, neuritic plaques and neurofibrillary tangles in the CA1 subfield of the hippocampus of control and ATD patients. The number of pyramidal cells per mm2 in the CA1 sector was significantly decreased in ATD cases as compared to controls, although there were large variations among cases. The most marked reductions in cell counts were observed in patients with a history of profound dementia. The densities of muscarinic receptors, as well as the proportions of M1 and M2 subtypes, in the CA1 sector and dentate gyrus were not significantly different between ATD and old non-demented patients. Neuritic plaques, even in high numbers, did not affect the density of muscarinic receptors; moreover, the densities of receptors over the neuritic plaques did not differ from the surrounding neuropil. However, in some ATD cases there was a marked decrease in the concentration of these receptors in the CA1 sector and subiculum, with no change in the proportions of muscarinic receptor sybtypes. These patients exhibited frequent extracellular remnants of neurofibrillary tangles (ghost tangles), but scarce neuritic plaques, and were those showing severe losses of pyramidal cells. There was a significant positive correlation between the total concentration of muscarinic receptors in the CA1 and the density of pyramidal cells, suggesting that decreases in receptor concentration result from a severe neuronal loss. We observed that the ratio of muscarinic receptors per pyramidal cell was significantly increased in ATD patients. This might indicate a possible up-regulatory mechanism for muscarinic receptors in the population of remaining neurons in ATD However, decreases of receptor numbers following severe neuronal fall out suggest that compensatory mechanisms are no longer possible in such cases. The question is raised whether these differences between cases reflect different diseases or different stages of the same disease.

Aged↗
PubMed2002

Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular amyloid depositions and senile plaques in Alzheimer's disease brains.

Heparan sulfate proteoglycans (HSPGs) may play a role in the formation and persistence of senile plaques and neurofibrillary tangles in Alzheimer's disease brains. Recently, it has been demonstrated that the human extracellular matrix-associated molecule collagen XVIII is the first collagen carrying heparan sulfate side-chains. Two variants of collagen XVIII with both different signal peptides and N-terminal domains have been described and are referred to as the short and long form. To investigate the distribution of these variants we performed an immunohistochemical analysis by using specific well-characterized polyclonal antibodies. Anti-long huXVIII, a polyclonal antibody directed against the long variant of collagen XVIII, weakly stained large cortical and leptomeningeal vessels, whereas small cortical vessels remained unstained. Interestingly, all amyloid-laden vessels and classic senile plaques were strongly stained. Anti-all huXVIII, a polyclonal antibody directed against an epitope common to both collagen XVIII variants, intensely stained all types of cerebral blood vessels, cerebral amyloid angiopathy-affected vessels and classic senile plaques. Collagen XVIII expression was absent in neurofibrillary tangles. We conclude that collagen XVIII is a novel heparan sulfate proteoglycan associated with vascular A beta and classic senile plaques and that at least the long form of collagen XVIII accumulates in amyloid-laden vessels and classic senile plaques.

Aged↗
PubMedDate not supplied

[Molecular biology of beta A4 protein and Alzheimer disease].

Senile plaques, neurofibrillary tangles and neuronal loss are the major histopathologic hallmarks of Alzheimer's disease. A prominent component of the senile plaques is a polypeptide (beta A4) of about 40 amino acids derived via proteolytic cleavage from a set of larger protein isoforms collectively referred to as the amyloid precursor protein (APP). The protein APP is a widely distributed transmembrane glycoprotein structurally related to a cell surface receptor. APP is encoded by a single gene on chromosome 21 in which missense mutations have been demonstrated in several cases of familial Alzheimer's disease. It is thought that various factors fostering the APP-processing pathway by which the polypeptide beta A4 is generated might be pathogenic. Thus the mechanisms that govern the rate of transcription of the APP gene, the differential splicing of the precursor messenger and the proteolytic processing of APP are current subjects of intensive investigation. Theoretically, each of these events represents a potential target for a therapeutic intervention. However, the relationships between amyloidogenesis and the formation of the neurofibrillary tangles associated to the neuronal loss remain to be elucidated.

Alzheimer Disease↗
PubMed1987

Brain amyloid in normal aging and cerebral amyloid angiopathy is antigenically related to Alzheimer's disease beta-protein.

Amyloid deposition is a prominent feature of a number of brain disorders, in which amyloid fibrils are found within blood vessel walls, the neuropil (neuritic plaques), neurons (neurofibrillary tangles). These include Alzheimer's disease (AD), AD changes associated with Down's syndrome, neurologically asymptomatic amyloidosis, Parkinson dementia of Guam, hereditary cerebral hemorrhage with amyloidosis of Icelandic origin (HCHWA-I), hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), and sporadic cerebral amyloid angiopathy (SCAA). Recently it was shown that the amyloid deposits in AD, Parkinson dementia of Guam, and HCHWA-D are formed by a similar 4-kd polypeptide called beta-protein. Because the nature of the amyloid deposits in other types of cerebral amyloidosis is not known, we have conducted immunocytochemical studies on brains from autopsy cases of AD, HCHWA-D, SCAA and neurologically asymptomatic elderly individuals. Brains from two subjects without neurologic involvement were used as controls. Sections from these specimens were incubated with rabbit polyclonal antibodies against 1) a synthetic peptide of 28 residues (anti-SP28), homologous to the NH2-terminal sequence of the beta-protein, 2) the main amyloid component of the HCHWA-I, a variant of cystatin C, and 3) purified fraction of neurofibrillary tangles. In all cases, anti-SP28 antibody specifically stained amyloid deposits in leptomeningeal and cortical vessels and neuritic plaques. These findings demonstrate that the amyloid deposits of SCAA and aged brains are composed of a protein antigenically similar to AD, HCHWA-D, and Parkinson dementia of Guam beta-protein, suggesting that all of these clinically and etiologically different morbid conditions are pathogenetically related. On this basis, they can be tentatively grouped as beta-protein deposition diseases. In addition, we found that HCHWA-D and SCAA vessels were mainly affected, while in AD parenchymal involvement predominates. These differences in the localization and extent of beta-protein deposits may account from the predominance of vascular complications in HCHWA-D and SCAA and of dementia in AD.

Aging↗
PubMed1997

Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein.

A proportion of the neuronal microtubule-associated protein (MAP) tau is highly phosphorylated in foetal and adult brain, whereas the majority of tau in the neurofibrillary tangles of Alzheimer's patients is hyperphosphorylated; many of the phosphorylation sites are serines or threonines followed by prolines. Several kinases phosphorylate tau at such sites in vitro. We have now shown that purified recombinant stress-activated protein kinase/c-Jun N-terminal kinase, a proline-directed kinase of the MAP kinase extended family, phosphorylates recombinant tau in vitro on threonine and serine residues. Western blots using antibodies to phosphorylation-dependent tau epitopes demonstrated that phosphorylation occurs in both of the main phosphorylated regions of tau protein. Unlike glycogen synthase kinase-3, the c-Jun N-terminal kinase readily phosphorylates Thr205 and Ser422, which are more highly phosphorylated in Alzheimer tau than in foetal or adult tau. Glycogen synthase kinase-3 may preferentially phosphorylate the sites found physiologically, in foetal and to a smaller extent in adult tau, whereas stress-activated/c-Jun N-terminal kinase and/or other members of the extended MAP kinase family may be responsible for pathological proline-directed phosphorylations. Inflammatory processes in Alzheimer brain might therefore contribute directly to the pathological formation of the hyperphosphorylated tau found in neurofibrillary tangles.

Antibody Specificity↗
PubMed2005

Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons.

Tau is a microtubule-associated protein enriched in the axonal compartment. In several neurodegenerative diseases including Alzheimer's disease, hyperphosphorylated tau accumulates in the somatodendritic compartment, self-aggregates, and forms neurofibrillary tangles. A fragmentation of the neuronal Golgi apparatus (GA) was also observed in Alzheimer's disease. In the present study, we examined the effect of overexpressing human tau on the organization of the neuronal GA in rat hippocampal cultures and in JNPL3 mice expressing tau mutant P301L. GA fragmentation was noted in a significantly higher percentage of hippocampal neurons overexpressing wild-type human tau than in control neurons over-expressing green fluorescent protein (GFP) alone. Most importantly, in neurons overexpressing mutant forms of human tau (P301L, V337M, or R406W), the percentage of neurons with a fragmented GA was 10% higher than that of neurons overexpressing wild-type human tau. In JNPL3 mice, a significantly higher percentage of motor neurons presented a fragmented GA compared to control mice. Interestingly, fragmentation of the GA was more frequent in neurons containing an accumulation and aggregation of hyperphosphorylated tau in the cell body than in neurons without these features. In both primary hippocampal neurons and JNPL3 mice, the tau-induced GA fragmentation was not caused by apoptosis. The pre-sent results implicate tau in GA fragmentation and show that this event occurs before the formation of neurofibrillary tangles.

Animals↗
PubMed2004

Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease.

Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.

Aged↗