Common Variant in <i>GRN</i> Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Abstract

Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

rs5848 Variant of Progranulin Gene Is a Risk of Alzheimer’s Disease in the Taiwanese Population

“…The T allele of rs5848 may decrease GRN protein expression in the brain, which accounts for the association of rs5848 variations with neurodegeneration. In a recent report, rs5848 variations were found leading to decreased levels of GRN and might be a risk factor for hippocampal sclerosis in patients with AD [12] .…”

Update on Hippocampal Sclerosis

“…This association was found in 72 % subjects in a cohort composed of 57 combined HS cases (HS + AD), which carried the T-allele for GNR rs5848, compared to AD cases without HS [12].…”

“…Representative published examples of inclusive criteria that are currently applied for establishing the neuropathologic diagnosis of HS are the following: B… HS defined as neuronal loss, spongy changes, and gliosis within region CA1 and the prosubiculum … [8]^; B… pure HS, defined as severe degeneration and gliosis of the CA1 sector and subiculum … in the absence of other dementing disease such as Alzheimer changes [4]^; BSevere neuronal loss in hippocampal field CA1 was required for inclusion in the series [9]^; B… severe neuronal loss with gliosis in the CA1 … and/or subiculum with relative sparing of the CA2/3 region [10]^; BHippocampal sclerosis is defined by marked loss of pyramidal neurons and gliosis in the CA1 and subiculum … [11]^; BHippocampal sclerosis (HpScl) was diagnosed on Hematoxylin & Eosin stained slides as the presence of neuronal loss in the subiculum and/or CA1 regions … out of proportion to the burden of NFTs present in these regions [12][13][14]^; BHS was defined as severe neuronal loss and gliosis in the hippocampal CA1 and/or subiculum [15•]^; BHS was operationalized as severe and selective neuronal loss and gliosis in CA1 and the subiculum, disproportionate to any degenerative pathology (e.g., Alzheimer or argyrophilic grain type pathologies) that might also be present [16]^; BHippocampal sclerosis was defined as complete or near-complete neuronal loss (only rare or widely scattered neurons remaining) in all or part of area CA1 … [6]^; or B… neuronal loss localized to the hippocampus, amygdala and entorhinal cortex [17]^.…”

“…(1) BHippocampal sclerosis was diagnosed on Hematoxylin & Eosin stained slides as the presence of neuronal loss in the subiculum and/or CA1 regions … out of proportion to the burden of neurofibrillary tangles present in these regions [12][13][14].…”

“…The function of GRN in the central nervous system is also not completely understood. It is expressed in neurons, glia, and endothelial cells, and mutations lead to a decrease in expression of progranulin [12], which could affect neuronal survival and inflammatory processes [37].…”