Milan, Italy

Istituto Nazionale Neurologico Carlo Besta

Participant 06: Istituto Nazionale Neurologico Carlo Besta
Division of Neuropathology and Neurology 5
Via Celoria 11
20133 Milano
Italy

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Project Leader


Dr. Giorgio Giaccone
Phone: +39 (2) 2394 260 
Fax: +39 (2) 7063 8217 
 
Dr. Giorgio Giaccone


Project Staff


Fabrizio Tagliavini
Supervision / Management/ Sampling / Neuropathology / Biochemistry / Preservation studies 

Michela Morbin
Sampling / Neuropathology / Microdissection 

Bianca Pollo
Sampling / Neuropathology / Microdissection 

Giacomina Rossi
Preservation studies / Biochemistry  

Giuseppe Di Fede
Doctoral students and technicians
Microdissection/ Preservation studies  

Lucia Limido
Microdissection / Biochemistry 

Silvia Suardi
Biochemistry / Preservation studies 

Michela Mangieri
Neuropathology/ Preservation studies 

Raffaella Capobianco
Neuropathology / Preservation studies 

Eleonora Canioni
Neuropathology 

Francesca Cacciatore
Neuropathology  

Spinello Sonia
Neuropathology  


Institute Presentation


Division of Neuropathology at the Istituto Neurologico Besta in Milan

Main activities of the Division of Neuropathology at the Istituto Neurologico Besta in Milan are clinical neuropathology, neurosurgical pathology and ultrastructural pathology, for diagnostic and research purposes.
The neuropathological collection and brain bank of histological slides, paraffin blocks and fixed nervous tissue specimens includes more than 1,200 brains and 20,000 neurosurgical biopsies.

The diseases which are represented in the collection are: Alzheimer's disease, prion diseases (sporadic and familial Creutzfeldt-Jakob disease, fatal familial insomnia), other neurodegenerative diseases such as sporadic (Pick's disease, progressive supranuclear palsy, corticobasal degeneration) and familial tauopathies.

Starting from 1996, the Division of Neuropathology and Neurology 5 of the Istituto Neurologico Besta is the reference center for surveillance of prion diseases of the Regione Lombardia. From this date, CJD brains have been systematically sampled, following an "ad hoc" protocol that allows a close correlation between histological/immunohistochemical and biochemical findings (Giaccone et al, Brain Pathology, 10:31-37, 2000; Puoti et al, Neurology, 53:2173-2176, 1999). The bank now holds more than 100 brains of patients with Creutzfeldt-Jakob disease, most of them characterized for polymorphic codon 129 of PRNP gene and for type of PrPres deposition in different brain areas.

In addition, the Division is carrying molecular genetics and biochemical analysis focused on degenrative dementias and prion diseases.

Major research interest

The research of the Division of Neuropathology is aimed to define the pathogenetic mechanisms of neuronal degeneration in the cerebral proteinoses: Alzheimer's disease and related disorders (Down syndrome, hereditary cerebral hemorrhage with amyloidosis), prion diseases (Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease) and tauopathies. These diseases are referred as cerebral proteinoses in that they are characterised by the accumulation in the nervous tissue of fragments (often amyloidogenic) of proteins as Aß precursor protein (APP), prion protein and tau protein. These fragments may be toxic to neurons, and responsible for neuronal degeneration and death that ultimately generate dysfunction of neuronal circuitry and clinical signs of disease. Cerebral proteinoses are sporadic and familial. In this case, they are often associated with specific mutations of DNA encoding for the abnormal protein that accumulates in the brain.

Our studies of patients with Alzheimer patients, Down syndrome and elderly individuals led to the identification of cerebral deposits of non-fibrillar material that are recognized by antibodies to Ab protein, but lack the optical, tinctorial and ultrastructural properties of amyloid and are not associated with neurofibrillary changes. It has been speculated that these deposits represent the earliest Alzheimer change, eventually evolving to the senile plaque and inducing neurofibrillary changes, if neurons vulnerable to develop such cytoskeletal alteration are available. The relatioship between Ab deposition in the neuropil and formation of neurofibrillary changes, made up of hyperphosphorylated tau protein was also investigated in other cerebral amyloidoses, as Gerstmann- Sträussler-Scheinker disease (GSS).

Biochemical and immunohistochemical studies were carried out in the Indiana kindred of GSS, a disease related to F198S mutation of the PRNP gene and characterized by PrP-amyloid and extensive neurofibrillary pathology, leading to the identification of the amyloidogenic peptide, to the definition of the structure of neurofibrillary degeneration and to the determination of the role of the mutant allele in the process of amyloidogenesis. Similar studies were carried out in other GSS genotypes (PRNP mutations P102L, A117V, and Q217R). Furthermore, after the biochemical characterization of the amyloidogenic fragment, significant peptides were synthetized and investigated for neurotoxicity in vitro. Finally, molecules able to lower experimental scrapie infectivity were identified and tested in vivo.

We also focused on hereditary cerebral hemorrhage with amyloidosis (HCHWA), an entity that differs from Alzheimer's disease for the prominent Ab deposition in the vessel wall and the absence of neurofibrillary changes. We have found four Italian families having several members dying in their 50's-60's for hemorrhagic stroke carrying a novel point mutation (Lys for Glu) at codon 693 of the APP770 gene. Despite a different mutation, Dutch and Italian families of HCHWA share basic clinical and neuropathological findings, suggesting that the site of the mutation is crucial to the phenotype.

The genetic screening of patients with familial dementia led to the identification of a new APP mutation (A713T) in the affected members of an Italian family with Alzheimer disease and severe congophilic angiopathy, a new tau mutation (P301S) in a family in which two affected members presented with frontotemporal dementia and corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to distinct clinical phenotypes and two novel extra-repeat insertional mutations of PRNP in patients with Creutzfeldt-Jakob disease.
This research was possible through a close collaboration between multiple complementary expertises developed by the Division or provided by others, and consisting in clinical activities (to select patients and families), neuropathology (to describe significant lesions), biochemistry (to characterize pathological proteins), molecular genetics (to identify relevant mutations).




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