Cholesterol in brain health and disease
Cholesterol is found in the cell membranes of all human cells. It plays an integral role in neuronal signaling and synaptic connections, especially in the brain. Notably, the brain contains between 20-25% of all the body’s cholesterol reserves, making it the organ with the highest cholesterol concentration in the human body. Interestingly, peripheral cholesterol (cholesterol absorbed from the diet that circulates in the bloodstream) is incapable of crossing the blood-brain barrier (BBB). Consequently, almost all of the brain’s cholesterol reserves arise from de-novo synthesis (in the glia and neurons). As humans age, the efficiency of their cholesterol-synthesizing glia and neurons diminishes, reducing their brains’ cholesterol reserves and resulting in impaired synaptic plasticity and overall synaptic loss. These losses have been suggested to contribute strongly to increased risks of neurodegenerative diseases.
These may include Alzheimer’s disease (ALD), Parkinson’s disease (PAD) and even Huntington’s disease (HUD). Unfortunately, the molecular and pathological mechanisms underpinning these observations remain understudied. In a recent review published in the journal Experimental & Molecular Medicine, researchers reviewed available literature on the role and mechanisms (molecular and pathological) by which cholesterol imbalances in the brain contribute to neurodegenerative disorders as mentioned above. They reviewed over 80 publications on critical mechanisms, including synaptic dysfunctions, oligomers of amyloid beta (Aβ) protein, protein clustering and membrane structure alterations, and α-synuclein aggregation. Their findings suggest that altered cholesterol synthesis and metabolism are shared features of most investigated neurodegenerative diseases.
There are recent data indicating that cholesterol synthesis is pivotal to maintain myelin integrity and this is necessary also to induce its repair in conditions like multiple sclerosis. Berghoff et al. (2021) demonstrated that microglìa enhances myelin lesions repair via acting on local cholesterol synthesis. They found that sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol thus activated liver X receptor (LXR) signaling to resolve inflammation, allowing oligodendrocytes to differentiate. This rise the question how clinically employed statins while improving the cardiovascular risk and/or outcomes, may actually enhance the risk for senile/cardiovascular dementia by compromising brain cholesterol homeostasis.
Molecular mechanisms involved
A – Membrane networks
Cholesterol has been observed to comprise up to 80% of the plasma membrane of synapses and is essential in both their formation and function. Research has highlighted that cholesterol imbalances can significantly alter the ability of synapses to share neurotransmissions effectively, eventually resulting in neurodegeneration. Molecular models have revealed that cholesterol imbalances adversely impact calcium-dependent vesicle fusion, altering membrane elasticity. In extreme cases, this can result in significant unwanted membrane bending and curvature alterations, increasing the energy required for membrane/vesicle fusion and impairing neurotransmission. Curvature and deformation are essential for vesicle function and fusion pore stabilization, enabling neurotransmission.
Recent rinvestigations have further revealed that cholesterol is critical in the protein clustering and intracellular organization of SNARE proteins. Communication between different SNARE proteins (like syntaxin-1A, SNAP-25 and VAMP-2) together comprises the core SNARE complex, which mediates vesicle fusion and thus neurotransmitter release. Cholesterol in also critical for “lipid rafts”, inner membrane anchored platforms enriched in sphingolipids, cellular receptors, protein adaptors, enzymes and other signal transduction proteins. Particulary, they have an elevated density for growth factor receptors, required for a proper neuronal trophism and survival.
An impaired presence of cholesterol, physically interacting also with specific lipid rafts proteins (e.g. caveolins) has benne demonstrated to compromise growth factor signaling and neuronal activities like neural plasticity, synapse remodeling, ionic currents, memory formation (particularly in hippocampus and amygdala of the brain). These activities, in turn, deepely affect the downstream gene expression which will sustain themselves and any form of neural responses to any external stimulus. Obviously, membrane and signaling defects are possible with either cholesterol excess (overload) and loss. This can be obtained with a massive employment of statins (to lower blood cholesterol), especially if associated to drugs like ezetimibe, that also impair choleterol absorption with diet.
B – Direct protein interactions
Beside lipid rafts and caveolin regulation, cholesterol may directyl binfd to many membrane proteins and receptors. This interaction is uoght by scientists not only to keep these proteins in the right place but to keep them in the suitable spatial conformation to allow them to work properly in their function. In transmembrane protein segments, the cholesterol recognition aminoacid consensus (CRAC) motif has been identified many years ago. CRAC is a relatively short, linear motif with the sequence (L/V)-X1–5-(Y)-X1–5-(K/R), where X represents any amino acid. K or R or even Y, are expected to hydrogen bond with cholesterol; the tyrosine aromatic ring structure stabilizes cholesterol’s polycyclic core by “stacking” against it, while Leu and Val interact with the hydrophobic lateral chain.
Lastly cholesterol and even some of its derivatives (e.g. cholesterol-3-sulphate) can directly regulate nuclear proteins, mostly transcription factors. Cholesterol-binding areas in soluble proteins are usually represented by protein hydrophobic cavities that shield the steroid from an aqueous environment and also enable cholesterol release to the membrane or a partner protein. An example is the sterol regulatory element-binding protein (SREBP-1) which possesses the lipid transfer domain called StART able to directly bind cholesterol. Another transcritpion factor affected by cholesterol is retinoid orphan receptor ROR-alpha, specifically affected more by the sulphate form, which serves as critical regulators of many physiological processes that occur during embryonic development and in adulthood, including regulation of circadian rhythms.
C – Interaction with of Aβ protein oligomers
The amyloid precursor protein (APP) is converted into Aβ protein via enzymatic cleavage catalyzed by β-secretase BACE1. Given its integral role in protein aggregation and folding, the successful conversion of APP to Aβ protein relies on normal cholesterol levels in the brain, with alterations in the latter observed to cause misfolding in the former. Misfolding of Aβ protein results in forming Aβ plaques, the accumulation of which is a hallmark of AD pathology. Cholesterol imbalance and elevated extracellular levels of cholesterol can promote the production and accumulation of Aβ peptides, which induce the formation of Aβ oligomers in the brain, thus contributing to neuronal damage and cognitive decline.
D – Pathological priotein aggregation (NF tangling)
Tau protein (specifically, hyperphosphorylated tau) aggregation, another hallmark of ALD pathology, is also contingent on cholesterol concentrations, given the membrane curvature properties of the latter. Recent research has elucidated that cholesterol-free membranes cannot form tau fibrils, while membranes containing cholesterol influence tau fibril formation contingent on cholesterol concentration and its associated membrane curvature. Unfortunately, the impacts of cholesterol on tau nucleation remain understudied and currently unknown. The genesis and progression of PAD are characterized by the accumulation of misfolded alpha-synuclein (α-syn) proteins in Lewy bodies (LEBs).
The mechanistic underpinnings of this process are a consequence of α-syn binding to membrane lipids. Imbalanced cholesterol accelerates α-syn aggregation and LEB formation, increasing the risk for PAD onset independently from the presence of enhancing protein mutations. Though, not definitively confirmed, the Western diet (enriched in carbohydrates, triglycerides and cholesterol and poor with fibers) is seemingly able to increase the risk for ALD and PAD onset. Some Authors also suspect that excessive cardiovascular use for statins may represent an additional risk factor for cholesterol inbalance in the brain to increase the former risk.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Shin KC, Ali Moussa HY, Park Y. Exp Mol Med. 2024 Aug 1.
Tong B, Ba Y et al. Neurobiol Dis. 2024 Jun; 196:106505.
Berghoff SA, Spieth L et al. Cell Rep. 2021; 37(4):109889.
Berghoff SA, Spieth L et al. Nat Neurosci. 2021; 24(1):47.
Fantini J et al. Protein Sci. 2020 Aug; 29(8):1748-1759.
Marin R, Fabelo N et al. Neurobiol Aging. 2017; 49:52-59.