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Bernardino Ghetti

Publications and source records attributed to Bernardino Ghetti.

At least 19 recordsLinked to original sources
PubMed2025

Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson's disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson's disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.

Humans↗
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2007

Performance on MMSE sub-items and education level in presenilin-1 mutation carriers without dementia.

BACKGROUND: Spanish-language screening tests that are sensitive to the early cognitive changes of Alzheimer's disease (AD) are needed. Persons known to be at 50% risk for young-onset AD due to presenilin-1 (PSEN1) mutations provide the opportunity to assess which measures on the Mini-mental State Examination (MMSE) are most sensitive to these early changes. METHODS: We performed genetic and Spanish-language cognitive testing on 50 Mexican persons without dementia at risk for inheriting PSEN1 mutations. We then compared the performance on sub-items of the MMSE between PSEN1 mutation carriers (MCs) and non-carriers (NCs) using t-tests and Fisher's exact tests. Exploratory multiple logistic regression analyses were also performed. RESULTS: Twenty-nine persons were MCs and 21 NCs. NCs tended to achieve higher levels of education (p = 0.039) than did MCs. MCs tended to perform more poorly when spelling "MUNDO" backwards and on Orientation, particularly regarding the date. In multiple regression analyses the ability of backwards spelling to predict PSEN1 mutation status was reduced when education was included as an independent variable. CONCLUSION: Subjects in the earliest stage of PSEN1-related AD showed deficits on orientation to date and in divided attention when spelling backwards. It is unclear if educational level should be considered an associated feature or a con-founding variable in this population although it should be taken into account when considering performance on the MMSE task of divided attention. The relative lack of deficits on delayed recall of three words probably represents the insensitivity of this measure in early AD. This study supports the utility of autosomal dominant AD as a model of the more common sporadic form of the disorder.

Aged↗
PubMed2006

The novel Tau mutation G335S: clinical, neuropathological and molecular characterization.

Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.

Adult↗
PubMed2006

Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.

Amyloid beta-Peptides↗
PubMed2006

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder, which has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996. The prevalence and incidence remain unknown but FTDP-17 is an extremely rare condition. It is caused by mutations in the tau gene, which encodes a microtubule-binding protein. Over 100 families with 38 different mutations in the tau gene have been identified worldwide. The phenotype of FTDP-17 varies not only between families carrying different mutations but also between and within families carrying the same mutations. The pathogenetic mechanisms underlying the disorder are thought to be related to the altered proportion of tau isoforms or to the ability of tau to bind microtubules and to promote microtubule assembly. Definitive diagnosis of FTDP-17 requires a combination of characteristic clinical and pathological features and molecular genetic analysis. Genetic counseling should be offered to affected and at-risk individuals; for most subtypes, penetrance is incomplete. Currently, treatment for FTDP-17 is only symptomatic and supportive. The prognosis and rate of the disease's progression vary considerably among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades.

Brain↗
PubMed2006

The A431E mutation in PSEN1 causing familial Alzheimer's disease originating in Jalisco State, Mexico: an additional fifteen families.

Nine families with autosomal dominant Alzheimer's disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.

Adult↗
PubMed2006

Aberrantly regulated proteins in frontotemporal dementia.

Non-Alzheimer's disease of the frontal type, or frontotemporal dementia (FTD), is the second most common form of dementia. Yet, a detailed characterization of the disease has been especially limiting. To identify mechanisms possibly involved in disease pathology or progression, a proteomic analysis of proteins isolated from human frontal cortex with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was performed. We used 2D gel electrophoresis and MALDI-TOF to identify a total of 24 proteins differentially expressed in FTDP-17. We identified a ubiquitin C-terminal hydrolase, UCHL1, as well as several proteins involved in oxidative stress to be differentially expressed. Data presented implicate UCHL1 and ubiquitin-mediated degradation as well as oxidative stress response in disease pathology or progression.

Chromosomes, Human, Pair 17↗
PubMed2006

Pathologic prion protein is specifically recognized in situ by a novel PrP conformational antibody.

Prion diseases are characterized by the accumulation in the brain of abnormal conformers (PrP(Sc)) of the cellular prion protein (PrP(C)). PrP(Sc) immunohistochemistry, currently based on antibodies non-distinguishing between PrP(C) and PrP(Sc), requires pre-treatments of histological sections to eliminate PrP(C) and to denature PrP(Sc). We employed the PrP(Sc)-specific antibody 89-112 PrP motif-grafted IgG on mildly fixed, untreated brain sections from several cases of human prion diseases. The results confirmed specific binding of IgG 89-112 to a structural determinant found exclusively on native disease-associated PrP conformations and lost following tissue denaturation or cross-linking fixation. Importantly, IgG 89-112 demonstrated no reactivity with normal brain tissue or with amyloid deposits in Alzheimer disease brain sections. Thus, immunohistochemical detection of native PrP(Sc) deposits was obtained by means of a PrP(Sc)-specific antibody. Such unique reagent may have many applications in the study of prion biology and in the diagnosis and prevention of prion diseases.

Amino Acid Motifs↗
PubMed2006

Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders.

Dysfunction of the 140 aa protein alpha-synuclein plays a central role in Lewy body disorders, including Parkinson's disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human alpha-synuclein(1-120), driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.

Animals↗
PubMed2006

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Adult↗
PubMed2006

Characteristics of frontotemporal dementia patients with a Progranulin mutation.

OBJECTIVE: Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined. METHODS: In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations. RESULTS: We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination. INTERPRETATION: Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer's disease.

Adolescent↗
PubMed2006

Gerstmann-Sträussler-Scheinker: a new phenotype with 'curly' PrP deposits.

Gerstmann-Sträussler-Scheinker (GSS) is a hereditary prion disease typically associated with prion protein (PrP)-containing plaques. The protease-resistant, scrapie PrP (PrPSc) is represented by internal fragments, whereas the C-terminal fragments associated with the other prion diseases are generally underrepresented. Different histopathologic and PrPSc features associated with at least 13 PrP gene (PRNP) mutations have been described in GSS. We report the histopathology and PrP characteristics in a father and son carrying a mutation at PRNP codon 187 that substitutes histidine (H) with arginine (R) and is coupled with valine (V) at position 129 (H187R-129V). The PrP plaques were present in both cases but with different structure and topography and minimal spongiform degeneration. A distinctive, "curly" PrP immunostaining was prominent in one case. The protease-resistant PrPSc differed in amount in the 2 cases, possibly depending on whether plaques or the curly immunostain was present. Two protease-resistant PrP fragments of 14 kDa and 7 kDa with, in at least one case, N-terminus between residues 90-99 and 82-90, respectively, codistributed with the plaques, whereas only very small amounts of the PK-resistant PrP were present in the curly staining regions. PK-resistant PrP recovered from the plaque and curly staining regions appeared to be full length.

Adult↗
PubMed2006

Cell-cycle markers in a transgenic mouse model of human tauopathy: increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1.

Recent evidence has suggested that an abnormal reactivation of the cell cycle may precede and cause the hyperphosphorylation and filament formation of tau protein in Alzheimer's disease and other tauopathies. Here we have analyzed the expression and/or activation of proteins involved in cell-cycle progression in the brain and spinal cord of mice transgenic for mutant human P301S tau protein. This mouse line recapitulates the essential molecular and cellular features of the human tauopathies, including hyperphosphorylation and filament formation of tau protein. None of the activators and co-activators of the cell cycle tested were overexpressed or activated in 5-month-old transgenic mice when compared to controls. By contrast, the levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 were increased in brain and spinal cord of transgenic mice. Both inhibitors accumulated in the cytoplasm of nerve cells, the majority of which contained inclusions made of hyperphosphorylated tau protein. A similar staining pattern for p21Cip1 and p27Kip1 was also present in the frontal cortex from a case of FTDP-17 with the P301L tau mutation. Thus, reactivation of the cell cycle was not involved in tau hyperphos-phorylation and filament formation, consistent with expression of p21Cip1 and p27Kip1 in tangle-bearing nerve cells.

Animals↗
PubMed2006

Neurodegeneration and hereditary dementias: 40 years of learning.

The invitation to participate in the commemorative issue celebrating the 100 th anniversary of Dr. Alois Alzheimer's report on the disease that would later bear his name has evoked memories of my early experiences in the study of dementia, my teachers, my role-models, my aspirations and my accomplishments. Early in my career, I was fascinated with the study of hereditary neurological disorders. The observation of families in which dementia was inherited in an autosomal dominant pattern excited my scientific curiosity. Three very different phenotypes in patients from three separate families have been the basis for novel scientific discovery, which has taken place over the past 30 years. This could not have taken place without the help of many generous patients and their families as well as wonderful colleagues for whom I am deeply grateful. Some of the original observations in these families have led to the discovery of genetic mutations in three genes that are among the most commonly affected in hereditary dementia. The work on these families has enriched the scientific community and our knowledge of dementing illnesses.

Amyloid beta-Protein Precursor↗
PubMed2006

Mutations in the tau gene (MAPT) in FTDP-17: the family with Multiple System Tauopathy with Presenile Dementia (MSTD).

Work in 1980s and early 1990s established that the microtubule-associated protein tau is the major component of the paired helical filament of Alzheimer's disease. Similar filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy, corticobasal degeneration and Pick's disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited "frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)". The paper highlighted here [Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737-7741] reported a mutation at position + 3 in the intron following alternatively spliced exon 10 of the tau gene in a family.

Alzheimer Disease↗