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| IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Clin Exp Med 2010;3(2):129-143
Review Article
Genetics and biology of Alzheimer’s disease and Frontotemporal Lobar
Degeneration
Daniela Galimberti, Elio Scarpini
Dept. of Neurological Sciences, "Dino Ferrari" Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore
Policlinico, Via F. Sforza 35, 20122, Milan, Italy
Received May 1, 2010, accepted May, 2010, available online May, 2010
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, whereas Frontotemporal Lobar
Degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. The two major neuropathologic
hallmarks of AD are extracellular Amyloid beta (A) plaques and intracellular neurofibrillary tangles (NFTs). Conversely, in FTLD the
deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for
ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include
the Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). The majority of mutations in these genes are often
associated with a very early onset (40-50 years of age). Regarding FTLD, the first mutations described are located in the Microtubule
Associated Protein Tau gene (MAPT). Tau is a component of microtubules, which represent the internal support structures for the
transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Mutations in MAPT are associated with an early onset of
the disease (40-50 years), and the clinical phenotype is consistent with Frontotemporal Dementia (FTD). Recently, mutations in a
second gene, named progranulin (GRN), have been identified in some families with FTLD. Progranulin is expressed in neurons and
microglia and displays anti-inflammatory properties. Nevertheless, it can be cleaved into granulins which, conversely, show
inflammatory properties. The pathology associated with these mutations is most frequently characterized by the immunostaining of
TAR DNA Binding Protein 43 (TDP-43), which is a transcription factor. The clinical phenotype associated with GRN mutations is highly
heterogeneous, including FTD, Progressive Aphasia, Corticobasal Syndrome, and AD. Age at disease onset is variable, ranging from
45 to 85 years of age. The majority of cases of AD and FTLD are however sporadic, and likely several genetic and environmental factors
contribute to their development. Concerning AD, it is known that the presence of the 4 allele of the Apolipoprotein E gene is a
susceptibility factor, increasing the risk of about 4 fold. A number of additional genetic factors, including cytokines, chemokines, Nitric
Oxide Synthases, contribute to the susceptibility for the disease. Some of them also influence the risk to develop FTLD. In this review,
current knowledge on molecular mechanisms at the basis of AD and FTLD, as well as the role of genetics, will be presented and
discussed. (IJCEM1005001).
Key words: Alzheimer’s disease, Frontotemporal Lobar Degeneration, mutation, genetics, amyloid, tau, TDP-43, inflammation,
oxidative damage
Full Text PDF
Address all correspondence to:
Daniela Galimberti, PhD
Department of Neurological Sciences
"Dino Ferrari" Center, University of Milan
Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico
Via F. Sforza 35, 20122
Milan, Italy
Tel: ++ 39.2.55033847
Fax: ++ 39.2.50320430
E-mail: daniela.galimberti@unimi.it
Review Article
Genetics and biology of Alzheimer’s disease and Frontotemporal Lobar
Degeneration
Daniela Galimberti, Elio Scarpini
Dept. of Neurological Sciences, "Dino Ferrari" Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore
Policlinico, Via F. Sforza 35, 20122, Milan, Italy
Received May 1, 2010, accepted May, 2010, available online May, 2010
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, whereas Frontotemporal Lobar
Degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. The two major neuropathologic
hallmarks of AD are extracellular Amyloid beta (A) plaques and intracellular neurofibrillary tangles (NFTs). Conversely, in FTLD the
deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for
ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include
the Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). The majority of mutations in these genes are often
associated with a very early onset (40-50 years of age). Regarding FTLD, the first mutations described are located in the Microtubule
Associated Protein Tau gene (MAPT). Tau is a component of microtubules, which represent the internal support structures for the
transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Mutations in MAPT are associated with an early onset of
the disease (40-50 years), and the clinical phenotype is consistent with Frontotemporal Dementia (FTD). Recently, mutations in a
second gene, named progranulin (GRN), have been identified in some families with FTLD. Progranulin is expressed in neurons and
microglia and displays anti-inflammatory properties. Nevertheless, it can be cleaved into granulins which, conversely, show
inflammatory properties. The pathology associated with these mutations is most frequently characterized by the immunostaining of
TAR DNA Binding Protein 43 (TDP-43), which is a transcription factor. The clinical phenotype associated with GRN mutations is highly
heterogeneous, including FTD, Progressive Aphasia, Corticobasal Syndrome, and AD. Age at disease onset is variable, ranging from
45 to 85 years of age. The majority of cases of AD and FTLD are however sporadic, and likely several genetic and environmental factors
contribute to their development. Concerning AD, it is known that the presence of the 4 allele of the Apolipoprotein E gene is a
susceptibility factor, increasing the risk of about 4 fold. A number of additional genetic factors, including cytokines, chemokines, Nitric
Oxide Synthases, contribute to the susceptibility for the disease. Some of them also influence the risk to develop FTLD. In this review,
current knowledge on molecular mechanisms at the basis of AD and FTLD, as well as the role of genetics, will be presented and
discussed. (IJCEM1005001).
Key words: Alzheimer’s disease, Frontotemporal Lobar Degeneration, mutation, genetics, amyloid, tau, TDP-43, inflammation,
oxidative damage
Full Text PDF
Address all correspondence to:
Daniela Galimberti, PhD
Department of Neurological Sciences
"Dino Ferrari" Center, University of Milan
Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico
Via F. Sforza 35, 20122
Milan, Italy
Tel: ++ 39.2.55033847
Fax: ++ 39.2.50320430
E-mail: daniela.galimberti@unimi.it
