Showing papers by "John Q. Trojanowski published in 2002"
TL;DR: Direct expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with α-synuclein in Drosophila and that interference with endogenous chaper one activity accelerated α- synuclein toxicity, suggesting chaperones may play a role in Parkinson's disease progression.
Abstract: Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha-synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.
1,175 citations
TL;DR: It is demonstrated that A53T α- synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.
1,070 citations
TL;DR: Levels of isoprostane 8,12-iso-iPF(2alpha)-VI found in cerebrospinal fluid, plasma, and urine of subjects with MCI imply that individuals withMCI have increased brain oxidative damage before the onset of symptomatic dementia.
Abstract: Background The isoprostane 8,12-iso-iPF2α-VI, a specific marker of in vivo lipid peroxidation, is increased in Alzheimer disease (AD). The pathological changes associated with AD have a long silent phase before the appearance of clinical symptoms. Several studies have shown that AD is preceded by a prodromal phase characterized by mild cognitive impairment (MCI). Objective To investigate levels of this biomarker in subjects with MCI. Design and Main Outcome Measures Using gas chromatography–mass spectrometry analysis, we measured 8,12-iso-iPF2α-VI levels in urine, plasma, and cerebrospinal fluid of patients with AD, subjects with MCI, and cognitively normal elderly subjects. Setting and Patients Subjects attending the Memory Disorders Clinic. Results We found significantly higher 8,12-iso-iPF2α-VI levels in cerebrospinal fluid, plasma, and urine of subjects with MCI compared with cognitively normal elderly subjects. Conclusions These results imply that individuals with MCI have increased brain oxidative damage before the onset of symptomatic dementia. Measurement of this isoprostane may identify a subgroup of patients with MCI with increased lipid peroxidation who are at increased risk to progress to symptomatic AD.
578 citations
TL;DR: The biochemical characteristics of the additional, higher molecular mass species of phosphorylated α-synuclein-positive polypeptides that also are recovered in the Sarkosyl-insoluble fraction of synucleinopathy and migrate at about 22 and 29 kDa suggest that phosphorylation of α- Synuclein is targeted to mono- and diubiquitination in synucle inopathy brains, which may have implications for mechanisms of these diseases.
375 citations
TL;DR: This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Aβ accumulation and oxidative stress, which it is suggested could work synergistically to promote the onset or drive the progression of AD.
Abstract: Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain Abeta deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased Abeta deposition as well as levels of Abeta and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Abeta accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.
342 citations
TL;DR: The authors detected misfolded α-synuclein in situ based on the proteinase K resistance (PK resistance) of αS fibrils, and using specific antibodies against S129-phosphorylated αS as well as oxidized αS.
Abstract: The pathological modifications of α-synuclein (αS) in Parkinson disease and related diseases are poorly understood. We have detected misfolded αS in situ based on the proteinase K resistance (PK resistance) of αS fibrils, and using specific antibodies against S129-phosphorylated αS as well as oxidized αS. Unexpectedly massive neuritic pathology was found in affected human brain regions, in addition to classical αS pathology. PK resistance and abnormal phosphorylation of αS developed with increasing age in (Thy1)-h[A30P] αS transgenic mice, concomitant with formation of argyrophilic, thioflavin S-positive, and electron-dense inclusions that were occasionally ubiquitinated. αS pathology in the transgenic mice was predominantly in the brainstem and spinal cord. Astrogliosis was found in these heavily affected tissues. Homozygous mice showed the same pathology approximately one year earlier. The transgenic mice showed a progressive deterioration of locomotor function.
314 citations
TL;DR: The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia withLewy bodies or pure dementia with Lewy bodies, and these α‐syn aggregates may contribute to the parkinsonism seen in these disorders.
Abstract: Intracytoplasmic inclusions composed of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative Lewy body disorders. Using novel monoclonal antibodies raised against altered alpha-syn, we uncovered an unprecedented and extensive burden of alpha-syn pathology in the striatum of Lewy body disorders. The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia with Lewy bodies or pure dementia with Lewy bodies, and these alpha-syn aggregates may contribute to the parkinsonism seen in these disorders.
310 citations
TL;DR: It can be surmised that oxidative/nitrative stress, which is cooperatively influenced by environmental factors, genetic predisposition, and senescence, may be a link between these disorders.
282 citations
TL;DR: It is indicated that dietary Al can modulate in vivo AD‐like amyloidosis in Tg2576 by increasing brain oxidative stress.
Abstract: SPECIFIC AIMAluminum (Al) exposure has been implicated in the Alzheimer’s disease (AD) pathogenesis and its known capacity to exacerbate oxidative events has been suggested as one possible mechanism of its neurotoxicity. To test this hypothesis, we fed transgenic mice overexpressing human amyloid precursor protein (Tg 2576) and wild-type (WT) littermates with a diet enriched in Al alone or in combination with the natural antioxidant vitamin E. Brain levels of the isoprostane 8,12-iso-iPF2α-VI, a specific marker of in vivo lipid peroxidation, as well as amyloid β peptide and deposition were measured.PRINCIPAL FINDINGS1. Dietary aluminum increases in vivo lipid peroxidationTg 2576 receiving a diet supplemented with Al showed an increase in 8,12-iso-iPF2α-VI urinary levels that occurred earlier and attained higher levels than Tg mice on regular chow. This increase was already significant after 6 months on the Al diet (3.1±0.1 vs. 2.2±0.06 ng/mg of creatinine, P<0.01) and was nearly doubled by 12 months of ag...
255 citations
TL;DR: First postmortem brain findings of a phase I clinical stroke trial patient implanted with human hNT neurons adjacent to a lacunar infarct 27 months after surgery indicate that implanted h NT neurons survive for >2 years in the human brain without deleterious effects.
Abstract: Although grafted cells may be promising therapy for stroke, survival of implanted neural cells in the brains of stroke patients has never been documented. Human NT2N (hNT) neurons derived from the NTera2 (NT2) teratocarcinoma cell line were shown to remain postmitotic, retain a neuronal phenotype, survive >1 year in host rodent brains and ameliorate motor and cognitive impairments in animal models of ischemic stroke. Here we report the first postmortem brain findings of a phase I clinical stroke trial patient implanted with human hNT neurons adjacent to a lacunar infarct 27 months after surgery. Neurofilament immunoreactive neurons were identified in the graft site, fluorescent in situ hybridization revealed polyploidy in groups of cells at this site just like polyploid hNT neurons in vitro, and there was no evidence of a neoplasm. These findings indicate that implanted hNT neurons survive for >2 years in the human brain without deleterious effects.
253 citations
TL;DR: It is suggested that it is important to recognize that the neurodegenerative process caused by the Ala53Thr mutation in α-synuclein is not identical to that seen in typical idiopathic Parkinson's disease brains.
Abstract: Previous genetic analysis of the familial Parkinson's disease Contursi kindred led to the identification of an Ala53Thr pathogenic mutation in the α-synuclein gene. We have re-examined one of the original brains from this kindred using new immunohistochemical reagents, thioflavin S staining and immunoelectron microscopy. Surprisingly, we uncovered a dense burden of α-synuclein neuritic pathology and rare Lewy bodies. Immunoelectron microscopy demonstrated fibrillar α-synuclein-immunoreactive aggregates. Unexpected tau neuritic and less frequent perikaryal inclusions were also observed. Some inclusions were comprised of both proteins with almost complete spatial disparity. We suggest that it is important to recognize that the neurodegenerative process caused by the Ala53Thr mutation in α-synuclein is not identical to that seen in typical idiopathic Parkinson's disease brains.
TL;DR: A preliminary expression profile of schizophrenia in defined neuronal populations is provided and understanding the coordinated involvement of multiple genes in human disease provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention.
Abstract: Background: Several lines of evidence indicate the altered function of the temporal lobe, including the hippocampus and entorhinal cortex (EC), is associated with schizophrenia. We used single-cell gene expression technologies to assess coordinate changes in the expression of multiple genes, including neuronal signaling and synaptic-related markers in EC layer II stellate neurons. Methods: We used a single-neuron microdissection technique coupled with linear antisense RNA amplification and high density/candidate gene arrays to assess coordinate changes in gene expression. The expression and relative abundance of more than 18000 messenger RNAs were assessed from EC layer II stellate neurons from postmortem samples of schizophrenic and age-matched control brains. Results of this initial screen were used to perform a more specific secondary messenger RNA screen for each subject. Results: Data disclosed marked differences in expression of various G-protein–coupled receptor-signaling transcripts, glutamate receptor subunits, synaptic proteins, and other transcripts. Results of secondary screening showed significant decreases in levels of G-protein subunit i1, glutamate receptor 3, N-methyl-D-aspartate receptor 1, synaptophysin, and sensory nerve action potentials 23 and 25 in the stellate neurons of schizophrenic patients. We observed down-regulation of phospholemman (a phosphoprotein associated with anion channel formation) messenger RNA and protein levels in layer II/III stellate neurons in the population with schizophrenia.
TL;DR: Data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.
Abstract: Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.
TL;DR: Analysis of soluble tau from different brain regions indicates that the mutation does not affect the ratio of tau isoforms synthesized, and the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain‐of‐function mechanism.
Abstract: MAPT, the gene encoding tau, was screened for mutations in 96 progressive supranuclear palsy subjects. A point mutation (R5L) was identified in a single progressive supranuclear palsy subject that was not in the other progressive supranuclear palsy subjects or in 96 controls. Functionally, this mutation alters the ability of tau to promote microtubule assembly. Analysis of soluble tau from different brain regions indicates that the mutation does not affect the ratio of tau isoforms synthesized. Aggregated insoluble tau from subcortical regions was predominantly four-repeat tau with no or one amino terminal insert (0N4R and 1N4R). Insoluble tau from cortical regions also contained 1N3R tau. Thus, the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain-of-function mechanism.
TL;DR: It is suggested that radioiodinated IMPY demonstrates desirable characteristics for in vivo labeling of Abeta plaques and it may be useful as a molecular imaging agent to study amyloidogenesis in the brain of living AD patients.
TL;DR: Pick's disease is characterized by an accumulations of Pick bodies in the hippocampal region and cortex as well as the presence of three and four microtubule‐binding repeat τ pathology in both cortical gray and white matter that distinguish this tauopathy from other neurodegenerative disorders.
Abstract: Pick's disease is characterized neuropathologically by distinct tau-immunoreactive intraneuronal inclusions known as Pick bodies and by insoluble tau proteins with predominantly three microtubule-binding repeat tau isoforms. However, recent immunohistochemical studies showed that the antibody specific for exon 10, which encodes the fourth microtubule-binding repeat, detected other tau lesions in Pick's disease. To better define the spectrum of tau pathology in Pick's disease, we used biochemical, immunohistochemical, and ultrastructural techniques to analyze the tau isoform composition in 14 Pick's disease brains. Western blot analysis showed that both three and four microtubule-binding repeat pathological tau isoforms are present in gray and white matter of various brain regions. Using phosphorylation-dependent anti-tau antibodies, we show that major tau phosphoepitopes are present in sarcosyl-insoluble gray and white matter regions of Pick's disease brains. Also, for the first time to our knowledge, we demonstrated that isoforms with four microtubule-binding repeat tau isoforms are present in Pick bodies from selected brains. Isolated tau filaments were straight or twisted and formed by three microtubule-binding repeat or four microtubule-binding repeat tau isoforms. Major tau phosphorylation-dependent and exon 10-specific epitopes were present in filaments. Therefore, Pick's disease is characterized by an accumulations of Pick bodies in the hippocampal region and cortex as well as the presence of three and four microtubule-binding repeat tau pathology in both cortical gray and white matter that distinguish this tauopathy from other neurodegenerative disorders.
TL;DR: Tau-positive glial lesions similar to human FTDs occur in these Tg mice, and these pathologies are linked to glial and axonal degeneration.
TL;DR: Analysis of transgenic mice that express human tau proteins have enabled in vivo quantitative assessments of axonal functions and have provided information about mechanistic relationships between pathological alteration of tau and axonal degeneration.
Abstract: The microtubule (MT)-associated protein (MAP) tau in neurons has been implicated as a significant factor in the axonal growth, development of neuronal polarity, and the maintenance of MT dynamics. Tau is localized to the axon, and is known to promote MT assembly and to stabilize axonal MTs. These functions of tau are primarily regulated by the activities of protein kinases and phosphatases. In Alzheimer's disease and other neurodegenerative disorders, abundant filamentous tau inclusions are found to be major neuropathological characteristics of these diseases. Both somato-dendritic and axonal tau lesions appear to be closely associated with axonal disruption. Furthermore, recent discoveries of pathogenic mutations on the tau gene suggest that abnormalities of tau alone are causative of neurodegeneration. Finally, analyses of transgenic mice that express human tau proteins have enabled in vivo quantitative assessments of axonal functions and have provided information about mechanistic relationships between pathological alteration of tau and axonal degeneration.
TL;DR: Although clinically heterogeneous, CBD is a distinct lobar and basal ganglionic tauopathy with selective aggregation of 4R-tau with similar burden of tau abnormalities in frontal, temporal, and parietal lobes and basal Ganglia of both hemispheres.
Abstract: Corticobasal degeneration (CBD) is an adult-onset progressive neurodegenerative disorder characterized by l-dopa-resistant rigidity, focal cortical deficits, and variable dementia The neuropathological hallmark of CBD is the deposition of filamentous inclusions in neurons and glia composed of hyperphosphorylated tau with only four microtubule-binding repeats (4R-tau) To characterize the regional burden of tau pathology in CBD, we studied 12 brains with the neuropathological diagnosis of CBD using biochemical and histochemical techniques Eleven brain regions were evaluated including gray and white matter from frontal, parietal, temporal, and occipital lobes and cerebellum as well as basal ganglia Although the distribution of tau pathology was variable, neuropathological and biochemical data showed a similar burden of tau abnormalities in frontal, temporal, and parietal lobes and basal ganglia of both hemispheres This included abundant, sarkosyl-insoluble 4R-tau in both gray and white matter of two or more of these cortical regions and basal ganglia, and to a lesser extent, cerebellar white matter The insoluble tau pathology in gray and white matter showed overlapping but distinct phosphorylated epitopes suggesting cell-type and subcellular localization (ie, cell bodies versus cell processes)-specific differences in tau phosphorylation In contrast, soluble tau was composed of normal 4R/3R-tau ratios indicating no gross abnormality in tau splicing Thus, although clinically heterogeneous, CBD is a distinct lobar and basal ganglionic tauopathy with selective aggregation of 4R-tau
TL;DR: The amygdala may be selectively vulnerable to developing both tau and α-synuclein pathology or tau pathology may predispose it to synuclein aggregation, thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.
Abstract: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD) A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have α-synuclein positive pathology, primarily in the amygdala We further characterized the tau and α-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques Tau pathology was readily detected in both affected and unaffected Chamorros In contrast, α-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD The α-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins Tau and α-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively Thus, the amygdala may be selectively vulnerable to developing both tau and α-synuclein pathology or tau pathology may predispose it to synuclein aggregation Furthermore, in PDC, tau and α-synuclein pathology occurs independent of β-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location
TL;DR: It is suggested that apoptosis contributes to cell death in both gray and white matter, and that decreases in cellular Bcl-2 may, in part, be associated with both apoptotic and non-apoptotic cell death following mild brain trauma.
TL;DR: The presence of a highly phosphorylated pool of τ in adult brain may modify the present hypotheses on how paired helical filaments of Alzheimer's disease are formed, and the turnover of phosphorylation sites on τ is rapid and depends on neuronal phosphatases.
Abstract: The extent of tau phosphorylation is thought to regulate the binding of tau to microtubules: Highly phosphorylated tau does not bind to tubules, whereas dephosphorylated tau can bind to microtubules. It is interesting that the extent of tau phosphorylation in vivo has not been accurately determined. Tau was rapidly isolated from human temporal neocortex and hippocampus, rhesus monkey temporal neocortex, and rat temporal neocortex and hippocampus under conditions that minimized dephosphorylation. In brain slices, we observed that tau isolated under such conditions largely existed in several phosphorylated states, including a pool that was highly phosphorylated; this was determined using epitope-specific monoclonal and polyclonal antibodies. This highly phosphorylated tau was dephosphorylated during a 120-min time course in vitro, presumably as a result of neuronal phosphatase activity. The slow-mobility forms of tau were shifted to faster-mobility forms following in vitro incubation with alkaline phosphatase. Laser densitometry was used to estimate the percent of tau in slow-mobility, highly phosphorylated forms. Approximately 25% of immunoreactive tau was present as slow-mobility (66- and 68-kDa) forms of tau. The percentage of immunoreactive tau in faster-mobility pools (42-54 kDa) increased in proportion to the decrease in content of 66-68-kDa tau as a function of neuronal phosphatases or alkaline phosphatase treatment. These data suggest that the turnover of phosphorylated sites on tau is rapid and depends on neuronal phosphatases. Furthermore, tau is highly phosphorylated in normal-appearing human, primate, and rodent brain.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Dramatic new insights into the role of alpha-synuclein (AS) in the pathobiology of PD have emerged recently, and this has led to the development of transgenic animal models of PD-like AS pathologies.
Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder. While the classic clinical-neuropathological features of PD have been well established, mechanisms underlying brain degeneration in PD are unknown, and only partially effective symptomatic treatments for PD exist. Further, there are no therapeutic interventions that prevent PD or block the progression of this relentless neurodegenerative disorder. However, dramatic new insights into the role of alpha-synuclein (AS) in the pathobiology of PD have emerged recently, and this has led to the development of transgenic animal models of PD-like AS pathologies. Continuing advances in this research direction should advance understanding of PD and accelerate discovery of more effective therapies for this and related synucleinopathies.
TL;DR: The discovery of multiple mutations in the tau gene that lead to the abnormal aggregation of tau and the onset/progression of FTDP-17 demonstrates that tau dysfunction is sufficient to produce neurodegenerative disease.
TL;DR: This article analyzed insoluble (pathological) τ proteins in five argyrophilic grain disease brains in comparison with those seen in Alzheimer's disease and Pick's disease, and found that pathological τ in ARG was confined primarily to mediotemporal neocortical gray and adjacent white matter, and also to the allocortex, amygdala and hippocampus.
Abstract: Although argyrophilic grain disease is characterized histopathologically by τ-positive lesions known as argyrophilic grains located predominantly in limbic brain regions in the absence of other diagnostic neuropathologies, the biochemical correlates of argyrophilic grains in gray and white matter have not been reported. Thus, we analyzed insoluble (pathological) τ proteins in five argyrophilic grain disease brains in comparison with those seen in Alzheimer's disease and Pick's disease. Analyses of separately dissected gray and white matter samples from various cortical regions revealed that pathological τ in argyrophilic grain disease was confined primarily to mediotemporal neocortical gray and adjacent white matter, and also to the allocortex, amygdala, and hippocampus. The amounts of sarcosyl-insoluble τ in all five cases were substantially lower than in Alzheimer's disease and Pick's disease, but the amounts of sarcosyl-insoluble τ in white matter were higher or comparable to that detected in gray matter from the same region, which distinguishes argyrophilic grain disease from Alzheimer's disease. The banding patterns of τ isoforms in argyrophilic grain disease varied: in three cases they were similar to Alzheimer's disease, but in two other cases, 4 microtubule binding repeat (4R) τ predominated, which distinguishes argyrophilic grain disease from classical Pick's disease. The differences between these three diseases were re-enforced by the predominance of straight τ filaments from argyrophilic grain disease brains. Thus, we conclude that argyrophilic grain disease is a distinct tauopathy characterized by prominent accumulation of argyrophilic grains in limbic brain regions in association with the characteristic τ biochemical and ultrastructural profile reported here.
TL;DR: The accumulation of -synuclein into filamentous inclusions appears to play a mechanistic role in the pathogenesis of several progressive neurological disorders including PD, dementia with LBs, Down’s syndrome, FAD, LB variant of AD, sporadic AD, multiple system atrophy, and other synucleinopathies.
Abstract: Recognition of a common mechanistic theme shared by Alzheimer’s disease (AD) and other neurodegenerative disorders began to emerge in the last decade, and because many of these disorders are characterized neuropathologically by intracellular and/or extracellular aggregates of proteinaceous fibrils that are implicated in progressive brain degeneration, these disorders may share similar targets for drug discovery. Thus, despite differences in the molecular composition of these filamentous lesions, growing evidence suggests that similar pathological mechanisms may underlie all of these disorders. More specifically, the onset and/or progression of brain degeneration in AD and other neurodegenerative disorders may be linked mechanistically to abnormal interactions between brain proteins that lead to their assembly into filaments and the aggregation of these filaments within brain cells or in the extracellular space. In sporadic and familial AD (FAD), these filamentous lesions are exemplified by intracytoplasmic neurofibrillary tangles (NFTs) and extracellular amyloid or senile plaques. Although filamentous lesions are recognized as diagnostic hallmarks of specific disorders, sporadic AD and FAD illustrate some of the complex and poorly understood overlap among these neurodegenerative diseases. For example, the heterogeneous dementing disorders classified as AD overlap with a large group of distinct neurodegenerative disorders (known as tauopathies) that are characterized by prominent -rich tangle pathology throughout the brain as well as with another diverse group of disorders (known as synucleinopathies) that are characterized by filamentous -synuclein brain pathology. Thus, whereas the diagnostic hallmarks of AD are numerous senile plaques composed of A fibrils and intraneuronal NFTs formed by aggregated filaments, NFTs are similar to the filamentous inclusions characteristic of neurodegenerative tauopathies, many of which do not show other diagnostic disease-specific lesions. Notably, gene mutations have been shown to cause familial frontotemporal dementia and parkinsonism linked to chromosome 17 in many kindreds. Moreover, whereas Lewy bodies (LBs) are regarded as hallmark intracytoplasmic neuronal inclusions of Parkinson’s disease (PD), they also occur in the most common subtype of AD known as the LB variant of AD, and numerous cortical LBs are the defining brain lesions of dementia with LBs, which is similar to AD clinically, but distinct from AD pathologically. Furthermore, -synuclein gene mutations cause familial PD in rare kindreds, and these mutations may be pathogenic by altering the properties of -synuclein, thereby promoting the formation of -synuclein filaments that aggregate into LBs. However, it is now known that FAD mutations and trisomy 21 lead to abundant accumulations of LBs composed of -synuclein filaments in the brains of most FAD and elderly Down’s syndrome patients, respectively, but it is unclear how these genetic abnormalities promote the formation of LBs from wild-type -synuclein proteins encoded by a normal gene. Nonetheless, the accumulation of -synuclein into filamentous inclusions appears to play a mechanistic role in the pathogenesis of several progressive neurological disorders including PD, dementia with LBs, Down’s syndrome, FAD, LB variant of AD, sporadic AD, multiple system atrophy, and other synucleinopathies. Thus, many neurodegenerative diseases share an enigmatic symmetry, that is, missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in sporadic variants of the disease. Accordingly, clarification of this enigmatic symmetry in any one of these disorders is likely to have a profound impact on understanding the mechanisms that underlie other of these diseases and on efforts to develop novel therapies to treat them. Moreover, AD is one of the more striking examples of a “triple brain amlyloidosis,” that is, a neurodegenerative disorder wherein at least three different building block proteins ( , -synuclein) or peptide fragments (A ) of a larger A precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (senile plaques) neurons. However, there are examples of other triple brain amyloidoses such as Down’s syndrome and Mariana Island dementia or Guam Parkinson’s dementia complex that also show evidence of accumulations of amyloid deposits formed by , -synuclein, and A , and there is increasing recognition that and -synuclein intraneuronal inclusions may converge with or without extracellular deposits of A in “double brain amyloidoses” as exemplified by the abundant inclusions in a member of the Contursi kindred with familial PD, or the co-occurrence of PD with abundant A deposits
TL;DR: There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects, and no tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.
Abstract: Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.
TL;DR: In the mouse model of mucopolysaccharidosis VII, it is found that specific regions of the brain are vulnerable to neurodegeneration, characterized by the presence of ubiquitin inclusions, neurofilamentInclusions, and reactive astrogliosis.
Abstract: The mucopolysaccharidoses are caused by inherited deficiencies of lysosomal enzymes involved in the degradative pathway of glycosaminoglycans. Lysosomal storage leads to cellular and organ dysfunction, including mental retardation. Storage lesions are found throughout the diseased brain, but little is known about the cellular and molecular mechanisms that underlie brain dysfunction. In the mouse model of mucopolysaccharidosis VII, we found that specific regions of the brain are vulnerable to neurodegeneration, characterized by the presence of ubiquitin inclusions, neurofilament inclusions, and reactive astrogliosis. The pathological lesions were found predominantly in the hippocampus and cerebral cortex, and they increased progressively with age. Treatment with a recombinant viral vector to correct the enzymatic defect quantitatively reversed the neurodegenerative lesions in targeted regions to normal levels.
TL;DR: Tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.
TL;DR: The Center for Neurodegenerative Disease Research (CNDR) organized a 1 day symposium entitled "Emerging Alzheimer's disease Therapies: Focusing On The Future" on November 7th, 2001 at the University of Pennsylvania in Philadelphia, PA, which focused on novel therapies for AD designed to prevent/eliminate Abeta deposits in the brains of AD patients.