Cholesterol storage and tau pathology in Niemann–Pick type C disease in the brain

Abstract

Niemann-Pick type C disease is an inherited neurovisceral storage disorder with intracellular accumulation of cholesterol. In affected brains, many ballooned neurons are seen. Considerable nerve cell loss of unknown pathogenesis leads to neurological deterioration and dementia. Chemical examination of brains has failed to demonstrate increased levels of cholesterol. Using filipin fluorometry of neuronal cells in tissue slices, we found massive accumulation of cholesterol in neurons in four out of five human Niemann-Pick type C cases including adult patients. Neurofibrillary tangles composed of aggregates of the otherwise highly soluble protein tau were present in three Niemann-Pick type C cases and were also immunologically identical to those associated with Alzheimer's disease. However, only a thin slab of spinal cord or a tiny piece of isocortex was available for examination in the two cases without tangles. In a further semi-quantitative analysis of 576 neurons, we determined higher cholesterol content in tangle-bearing neurons than in adjacent tangle-free neurons. The association of cholesterol accumulation with neurofibrillary degeneration in Niemann-Pick type C disease and Alzheimer's disease awakens interest in the role of impaired cholesterol metabolism in the development of neurofibrillary tangles in both diseases.

Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse Brain

“…12,14 In both diseases, levels of free cholesterol are positively correlated with the incidence of intraneuronal neurofibrillary tangles. 16,17 Several lines of evidence have established lysosomal dysfunction as an early-onset neuropathological feature of AD. Levels of lysosomal cathepsin D in neurons are increased in AD vulnerable regions before the onset of major pathology.…”

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

“…BSN protein reportedly regulates the degradation of multiple presynaptic proteins through ubiquitination and autophagy 35,36 . Regarding tauopathy, some genetic mutations involved 37 . Additionally, several genetic mutations outside the MAPT gene are reportedly associated with tauopathy 38 .…”

Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits

“…In support, (1) endolysosomes are the major site, where Aβ is produced [52,53], and endolysosome dysfunction leads to brain deposition of Aβ [17]; (2) Endolysosomes are responsible for synaptic protein recycling [54][55][56], and endolysosome dysfunction leads to disruption of synaptic integrity in brain [57][58][59][60][61]; (3) Tau can be degraded by cathepsin D in autophagosomes-lysosomes [62][63][64][65] and increased levels of endolysosome cholesterol, as occurs in Niemann-Pick type C disease, leads to lysosome dysfunction and tau-pathology [66][67][68][69][70][71]. Substantial evidence from human epidemiological studies and from experimental studies conducted in animals and cultured cell models indicate that caffeine, when ingested chronically, can decrease Aβ levels, protect against the onset and severity of AD, and in some cases it can reverse behavioral and pathological features of AD [19,21,24,29].…”