Neurofibrillary tangles in Niemann-Pick disease type C

Abstract

Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with beta-amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and consisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.

Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain

“…Finally, TLR4 has been implicated in glial cell activation that occurs in other, more common neurodegenerative diseases including Alzheimer's disease (Kakimura et al, 2002). NPC and Alzheimer's disease share several pathological features including the formation of neurofibrillary tangles (Suzuki et al, 1995) and the accumulation of ␤-amyloid (Saito et al, 2002), suggesting the presence of common biochemical mechanisms involved in the pathogenesis of these two diseases. Activation of TLR4 and downstream signaling events may be one of the common biochemical mechanisms involved in glial cell activation that occurs in the brains of NPC and Alzheimer's disease.…”

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

“…Granules with improper pigment balance due to white, brown, or scarlet mutations become autolysosomes (Shoup 1966;Stark and Sapp 1988). Lysosomal dysregulation is a characteristic feature of Niemann-Pick disease type C and Sanfillipo syndrome type B, both tauopathies Sokol et al 1988;Suzuki et al 1995;Ohmi et al 2009). Additionally, Dermaut et al (2005) showed that abnormal loss-of-function mutations in benchwarmer, which are associated with enlarged lysosomes, also dose dependently enhance tau toxicity.…”

Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

“…15) via the modulation of amyloid-␤ synthesis (16,17). Other lines of evidence suggest that cholesterol plays essential roles in the modulation of tau phosphorylation (6,18,19), neurofibrillary tangle formation (20), and neuronal survival (21,22). These lines of evidence suggest that Alzheimer disease pathologies preferentially developing in specific brain regions may be explained by a region-specific difference in the lipid profile.…”