Neurodegenerative Disease Alzheimer’s Disease


Genetics and Molecular Biology of Alzheimer’s Disease and Frontotemporal Lobar Degeneration


Daniela Galimberti,1 Chiara Fenoglio1 and Elio Scarpini2 1. PhD Researcher; 2. Professor of Neurology, Department of Neurological Science, ‘Dino Ferrari’ Centre, University of Milan


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 pre-senile onset. The two major neuropathological hallmarks of AD are extracellular amyloid beta plaques and intracellular neurofibrillary tangles. 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), whereas the main genes responsible for familial FTLD are microtubule-associated protein tau gene (MAPT) and progranulin (GRN). Concerning sporadic AD, it is known that the presence of the ε4 allele of the apolipoprotein E gene is a susceptibility factor. A number of additional genetic factors contribute to susceptibility for AD and FTLD.


Keywords Alzheimer’s disease, frontotemporal lobar degeneration, mutation, genetics, amyloid, tau, TDP-43, inflammation, oxidative damage


Disclosure: The authors have no conflicts of interest to declare. Received: 20 April 2010 Accepted: 29 June 2010 Citation: European Neurological Review, 2010;5(1):12–6 Correspondence: Daniela Galimberti, Department of Neurological Sciences, ‘Dino Ferrari’ Centre, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F Sforza 35, 20122 Milan, Italy. E: daniela.galimberti@unimi.it


Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, with a prevalence of 5% after 65 years of age. The disease was originally described by Alois Alzheimer and Gaetano Perusini in 1906, and it is clinically characterised by progressive cognitive impairment including impaired judgement, decision-making and orientation, often accompanied, in later stages, by psychobehavioural disturbances as well as language impairment. The two major neuropathological hallmarks of AD are extracellular beta-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The production of Aβ, which represents a crucial step in AD pathogenesis, is the result of the cleavage of a bigger precursor, named amyloid precursor protein (APP), which is overexpressed in AD.1


Aβ forms highly insoluble and proteolysis-resistant fibrils known as ‘senile plaques’.


NFTs are composed of the tau protein. In healthy controls, tau is a component of microtubules, which are the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilise the growing axons, which are necessary for the development and growth of neurites.1


In AD, tau


protein is abnormally hyperphosphorylated and forms insoluble fibrils, which originate deposits within the cell.


Frontotemporal lobar degeneration (FTLD) occurs most often in the pre-senile period, and age at onset is typically 45–65 years, with a mean in the 50s. Distinctive features in FTLD concern behaviour, including disinhibition, loss of social awareness, overeating and impulsiveness. Despite profound behavioural changes, memory is relatively spared.2


In contrast to AD, which is more frequent in women, 12


FTLD has an equal distribution among men and women. The current consensus criteria3


and SD is associated with loss of knowledge about words and objects. This variability is determined by the relative involvement of the frontal and temporal lobes, as well as by the involvement of right and left hemispheres.5


identify three clinical syndromes: frontotemporal dementia (FTD), progressive non-fluent aphasia (PA) and semantic dementia (SD), which reflect the clinical heterogeneity of FTLD. FTD is characterised by behavioural abnormalities, whereas PA is associated with progressive loss of speech, with hesitant, non-fluent speech output,4


Despite the majority of AD and FTLD cases being sporadic and likely caused by the interaction between genetic and environmental factors, so far it has been observed that clinically typical AD and FTLD can cluster in families and be inherited in an autosomal dominant fashion, suggesting a genetic cause.


Familial Alzheimer’s Disease


In 1987, a region of linkage with AD was reported on the long arm of chromosome 21, which encompassed a region harboring the β-APP gene, a compelling candidate for AD.6


chromosome 21q21.22 and encodes for a transmembrane protein that is normally processed into amyloid fragments. In 1991, the first missense mutation in APP was reported.7


mutations have been described in the β-APP (www.molgen.ua.ac.be/). All of these mutations cause amino acid changes in putative sites for the cleavage of the protein, thus altering the APP processing, such that more pathological Aβ42 is produced.8


The gene is located at Since then, 32 different


Interestingly, chromosome © TOUCH BRIEFINGS 2010


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