Metals and cholesterol: two sides of the same coin in Alzheimer’s disease pathology

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of β-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed.

Unusual Cyclodextrin Derivatives as a New Avenue to Modulate Self‐ and Metal‐Induced Aβ Aggregation

“…Moreover, there are tailing peaks in the range m/z 1660-1725 corresponding to Cu 2 + -Ab 1-16 -CD3HQ ternary complexes. Similar results were found in the case of the difunctionalized CyD derivatives as well as in the case of Zn 2 + -Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] .T he interaction of metal-Ab with CyD-OHQ derivatives was also monitored by UV/Vis spectroscopy.T he spectra of Cu-CyD-OHQ and Cu-Ab 1-16 -CyD-OHQ systems are not superimposable (the Supporting Information, Figures S27 and S28), suggesting the competition of the CyD-OHQ derivativew ith Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] for the metal ion. The UV/Vis data are consistentwith the ESI-MSf indings.…”

“…Directi nteraction of the ligands with metal-Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Because AD is characterized by the accumulation of metal ions (such as Cu 2 + and Zn 2 + )i ns enile plaques and that these biometals influence the fibrillation and toxicity of Ab peptides, [56] the direct interaction of Cu 2 + -Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] or Zn 2 + -Ab 1-16 and the new CyD-OHQ conjugates was evaluated through ESI-MS and UV/Vis spectroscopy.A b 1-16 was used as am odel of amyloid peptides because it containst he Cu 2 + and Zn 2 + coordination sites of the N-terminus of Ab peptides, considered to be independento fa myloid length. As previously reported, [22] the mass spectrum of a1:1 mixture of Ab [1][2][3][4][5][6][7][8][9][10][11][12][13]…”

“…[10] In particular, b-CyD, consisting of seven glucose units,i s able to interact with Ab and substantially decrease its neurotoxic effects in vitro [11,12] and in vivo. [13] Disruption of metal and cholesterol homeostasis are two majorp athologicalf eatures in neurodegeneratived isorders such as Alzheimer's disease (AD), [14][15][16] Parkinson's disease (PD), [17] as well as NPC. [18] Nevertheless, native CyDs are not able to complex metal ions at physiological pH.…”

Cyclodextrin 3‐Functionalized with 8‐Hydroxyquinoline as an Antioxidant Inhibitor of Metal‐Induced Amyloid Aggregation

“…[18] Interestingly, b-CyD acts in synergyw ith curcumin to suppress a-synuclein aggregation (involved in Parkinson's disease) and breaks up the preformed aggregates almost completely. [19] Disruption of metal and cholesterol homeostasis, protein misfolding, and aggregation are recognized among the major pathological features in triggering neurodegenerativedisorders such as Alzheimer's disease (AD), [20][21][22] Parkinson's disease (PD), [23] and NPC. [24] Nevertheless, native CyDs are not able to complex metal ions because of the poor coordinating ability of the hydroxyl groupsa tp hysiological pH.…”

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice

“…While it comprises approximately 2% of total body weight, it disproportionately consists of 25% of the body’s total cholesterol (Haroutunian et al 2014). Cholesterol alters lipid membrane fluidity, function, and is critical in the formation and stability of lipid rafts (Wong et al 2014), glycolipoprotein microdomian coordination centers for the assembly of signaling molecules, signal transduction processes, and protein trafficking. These regions are enriched in cholesterol and sphingomyelins as required elements to tightly pack, enhance rigidity, and reduce the fluidity of the lipid bilayer.…”