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

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.

Dendritic protein synthesis in the normal and diseased brain

“…The dendritic RNA binding protein TDP-43 is a component of intracellular inclusions found in patients with neurodegenerative diseases such as frontotemporal lobe dementia and Alzheimer’s disease (Galimberti and Scarpini, 2010, Wilson et al, 2011). While it is has been suggested that TDP-43 regulates mRNA translation and is localized to dendrites in an activity-dependent manner (Wang et al, 2008a), it is unclear whether dendritic mRNA localization or local translation are dysregulated by altered TDP-43 function.…”

Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients

“…Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease 1 , and frontotemporal dementia (FTD) 2 , the most frequent presenile onset neurodegenerative disorder, now belong to a class of neurological conditions caused by repeat expansions, owing to the 2011 discovery that an expanded hexanucleotide (GGGGCC) repeat within a non-coding region of the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the major genetic cause of both disorders, collectively referred to as c9FTD/ALS (OMIM *614260). Because repeat expansions causing other neurodegenerative diseases are known to alter epigenetic mechanisms while simultaneously leading to toxic RNA gain-of-function (GOF) and protein loss-of-function (LOF) 3 , researchers now seek to elucidate whether GOF and/or LOF mechanisms contribute to c9FTD/ALS.…”

Familial Frontotemporal Dementia-AssociatedPresenilin-1 c.548G>TMutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice

“…For example, tau pathology is present in some FTD cases whereas others lack tau deposition. A large proportion (~20–50%) of FTD cases have a familial component, and mutations in microtubule-associated protein tau and progranulin genes are the most frequent genetic causes (Galimberti and Scarpini, 2010). Interestingly, mutations in the presenilin-1 ( PSEN1 ) and presenilin-2 ( PSEN2 ) genes, which are the major cause of familial AD, have also been implicated in FTD (Mendez and McMurtray, 2006).…”