Neurofibrillary tangles in Niemann—Pick disease type C

Abstract

Post-mortem neuropathological examination of five cases of Niemann-Pick disease type C revealed neurofibrillary tangles in many parts of the brain. Tangles were a consistent finding in the hippocampus, hypothalamus, substantia innominata, midbrain pons and medulla. Other regions of the brain in which tangles were present included neocortex, basal ganglia, thalamus, cerebellar cortex in one case, and dentate nucleus in another. The tangles were argyrophilic, fluoresced under ultraviolet light when stained with thioflavin S, and reacted strongly with antibody to tau protein. Some of the tangles could be immunostained for ubiquitin. Electron microscopy, performed in one of the cases, showed the tangles to consist of paired helical filaments ultrastructurally identical to those of Alzheimer's disease. The distribution of the tangles in the central nervous system as a whole and also within many individual neurons corresponded fairly closely with that of the abnormal storage material. Both the tangles and the storage material extended into, and distended, the proximal parts of many dendrites and axons. No A4/beta protein, either in the form of plaques or in the walls of blood vessels, was detected in any of the cases. Our findings suggest that neurofibrillary tangles are a common feature of Niemann-Pick disease type C and that their formation may be a reaction to the abnormal storage material.

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

“…Given the apparent sensitivity of the A allele to SREBP-2 mediated regulation, in the presence of APOE 4 this may lead to a scenario where cholesterol is produced but not secreted, leading to cholesterol based dysfunction of astroglial cells. It is noteworthy that such astroglial activation occurs in Niemann Pick Disease Type-C, a cholesterol storage disease that presents histologically with neurofibrillary tangles identical to those in AD (Love et al, 1995). In support of potential interactions between APOE and HMGCR, a recent study by Recuero et al (Recuero et al, 2009) found that there was a trend towards a link between an a 3' SNP in the HMGCR gene and APOE, in that the greatest decrease in risk was present in APOE 4 carrier women.…”

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

“…The latter have greatly facilitated investigation of tau hyperphosphorylation in diseases other than AD. It thus has been shown that lesions made of hyperphosphorylated tau similar to those found in AD are present in Down syndrome (11), Niemann-Pick disease type C (12)(13)(14), Gerstmann-Sträussler-Scheinker (GSS) disease with tangles (15,16), prion protein amyloid angiopathy (17), parkinsonism-dementia complex of Guam (18,19), and familial presenile dementia with tangles (20,21).…”

Lipid metabolism in Alzheimer’s disease

“…A cholesterol-enriched diet enhances tau phosphorylation and aggregation in a Tau mutant mouse model [101] . Deletion of NPC1, involved in cholesterol transport and esterifi cation, leads to the accumulation of free cholesterol and increased levels of hyperphosphorylated tau [102] . Further, kinases for tau, such as CDK5, are upregulated in NPC1-deficient cells [103,104] .…”