Cholesterol and Synaptic Compensatory Mechanisms in Alzheimer's Disease Mice Brain During Aging

Abstract

Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-β deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AβPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AβPP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AβPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology.

Age-Related Alterations in the Metabolic Profile in the Hippocampus of the Senescence-Accelerated Mouse Prone 8: A Spontaneous Alzheimer's Disease Mouse Model

“…In cell culture systems, the production of Aβ is modulated by cholesterol, and studies using animal models have consistently demonstrated that hypercholesterolemia is associated with an increased deposition of cerebral Aβ peptides [24]. The link between cholesterol levels and AD is also amplified by the finding that many proteins involved in cholesterol metabolism, such as liver X receptor (LXR), have been shown to be associated with late onset AD [7, 25]. One study indicated that the application of a cholesterol-reducing LXR agonist improved the quantity of presynaptic boutons [7], regulated neuroinflammation, and decreased Aβ accumulation [26].…”

“…The link between cholesterol levels and AD is also amplified by the finding that many proteins involved in cholesterol metabolism, such as liver X receptor (LXR), have been shown to be associated with late onset AD [7, 25]. One study indicated that the application of a cholesterol-reducing LXR agonist improved the quantity of presynaptic boutons [7], regulated neuroinflammation, and decreased Aβ accumulation [26]. The administration of statins has also been demonstrated to protect against AD [27, 28].…”

“…The abnormalities in cerebral metabolism in AD throughout aging have been gradually documented over recent years. Metabolic abnormalities in AD that have been described include abnormal lipid metabolism [6], such as cholesterol metabolic dysfunction [7, 8]. Significant deficits in mitochondrial bioenergetic pathways have also been reported [9, 10].…”

Plant sterols: Friend or foe in CNS disorders?

“…The amyloidogenic pathway is predominantly associated with lipid rafts, whereas the non-amyloidogenic pathway is correlated with non-lipid rafts [119,120]. Accumulating evidence suggests a key role for a disturbed CNS cholesterol homeostasis in the development and progression of AD [121][122][123][124][125][126][127]. In this section, we elaborate on the impact of sterol metabolism on the development and progression of AD, and discuss how phytosterols may impact AD pathology.…”

Effect of perinatally supplemented flavonoids on brain structure, circulation, cognition, and metabolism in C57BL/6J mice

“…Immunohistochemistry was performed using standard freefloating labeling procedures, using the protocol described by Jansen et al (2012Jansen et al ( , 2014 and Janssen et al (2015). For DCX, polyclonal goat anti-doublecortin (1:4000; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) was used as a primary antibody to assess neurogenesis.…”