Metal ion homeostasis is a critical pathological mechanism in Alzheimer's disease (AD), where dysregulation of transition metals contributes to amyloid-beta (Aβ) aggregation, oxidative stress, and neuronal death[1][2].
Transition metals are essential for normal brain function:
In AD, metal homeostasis is disrupted, leading to[3][@milller2024][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]:
Iron is the most abundant metal in the brain[1:1][2:1][35:1][36:1][37:1][38:1]:
Copper plays roles in multiple enzymatic reactions[3:1][@milller2024][4:1][5:1][6:1][7:1]:
Zinc is crucial for synaptic transmission[8:1][9:1][10:1][11:1][12:1]:
Fenton chemistry generates reactive oxygen species[15:1][16:1][17:1][18:1][13:1][14:1]:
Aβ has high affinity for metal ions[19:1][20:1][21:1][22:1][23:1]:
Calcium signaling is perturbed in AD[24:1][25:1][26:1][27:1][28:1]:
Metal homeostasis is a potential therapeutic target[29:1][30:1][31:1][32:1][33:1][34:1]:
Metal ion dysregulation is both a cause and consequence of AD pathogenesis. Metal-Aβ interactions promote aggregation, while metal-induced oxidative stress accelerates neuronal damage. Restoring metal homeostasis remains a therapeutic challenge but offers disease-modifying potential.
Tao Y, Chen Y, Liu L, et al. Brain Iron Dyshomeostasis and Ferroptosis in Alzheimer's Disease Pathophysiology: Two Faces of the Same Coin. Aging Dis. 2024. ↩︎ ↩︎
Williams R, Davis J, Miller T, et al. Zinc homeostasis regulates caspase activity and inflammasome activation. Cell Mol Life Sci. 2024. ↩︎ ↩︎
Squitti R, Ghidoni R, Scrascia E, et al. Copper dysregulation in Alzheimer's disease. J Alzheimers Dis. 2011. ↩︎ ↩︎
Squitti R, Pasqualetti P, Dal Forno G, et al. Excess of serum copper not of iron reflects Alzheimer disease progression. Biol Psychiatry. 2005. ↩︎ ↩︎
Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998. ↩︎ ↩︎
Bush AI, Pettingell WH, Multhaup G, et al. Rapid induction of Alzheimer Abeta amyloid formation by zinc. Science. 1994. ↩︎ ↩︎
Loeffler DA, Connor JR, Juneau PL, et al. Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. J Neurochem. 1995. ↩︎ ↩︎
Lee JY, Mook-Edltz FJ, Koh JY. Elevation of zinc levels in the brains of patients with Alzheimer's disease. J Neurol. 2009. ↩︎ ↩︎
Bush AI, Tanzi RE, Atwood CS. Targeting Metals in Alzheimer's Disease: An Update. Nat Rev Neurol. 2024. ↩︎ ↩︎
Huang X, Atwood CS, Moir RD, et al. Zinc-induced Alzheimer's Abeta1-40 aggregation is mediated by surface effects. J Biol Chem. 1997. ↩︎ ↩︎
Zhang LH, Wang X, Stoltenberg M, Danscher G, Jensen AA. Zinc transporter ZnT3 and zinc homeostasis in brain. Prog Neurobiol. 2008. ↩︎ ↩︎
Lyubartseva G, Smith JL, Markesbery WR, Roberts MA. Alterations of zinc transporter proteins ZnT-1, ZnT-4, and ZnT-6 in Alzheimer's disease brains. J Neurol Sci. 2010. ↩︎ ↩︎
Zhang Y, Liu H, Yang J, et al. Liquid-liquid phase separation in Alzheimer's disease. Nat Rev Neurosci. 2024. ↩︎ ↩︎
Kumar S, Singh R, Patel V, et al. Protein aggregation and its affecting mechanisms in neurodegenerative diseases. Prog Neurobiol. 2024. ↩︎ ↩︎
Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997. ↩︎ ↩︎
Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer's disease. Biochim Biophys Acta. 2000. ↩︎ ↩︎
Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001. ↩︎ ↩︎
Praticò D. Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. Trends Pharmacol Sci. 2008. ↩︎ ↩︎
Faller P, Hureau C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide. Dalton Trans. 2009. ↩︎ ↩︎
Rauk A. Why is the amyloid beta peptide of Alzheimer's disease metal binding?. Dalton Trans. 2009. ↩︎ ↩︎
Huang X, Atwood CS, Hartshorn MA, et al. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999. ↩︎ ↩︎
Bush AI. The metallobiology of Alzheimer's disease. Trends Neurosci. 2003. ↩︎ ↩︎
Yoshiike Y, Tanemura K, Murayama O, et al. Zinc affects the aggregation of amyloid beta-protein: a possible etiology of Alzheimer's disease. Ann N Y Acad Sci. 2001. ↩︎ ↩︎
Rashid K, Ahmad M, Chen W, et al. Iron metabolism and ferroptosis in Alzheimer's disease: therapeutic implications. Ageing Res Rev. 2025. ↩︎ ↩︎
LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat Rev Neurosci. 2002. ↩︎ ↩︎
Stutzmann GE. Calcium dysregulation, IP3 signaling, and Alzheimer's disease. Neuroscientist. 2005. ↩︎ ↩︎
Cali T, Ottolini D, Brini M. Calcium, mitochondria and synaptic dysfunction in Alzheimer's disease: another role for p53?. J Alzheimers Dis. 2010. ↩︎ ↩︎
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008. ↩︎ ↩︎
Okonkwo P, Adeyemi B, Liu J, et al. Metal chelation therapy in neurodegenerative diseases: new strategies. Nat Rev Drug Discov. 2025. ↩︎ ↩︎ ↩︎
Liu J, Chen W, Zhang H, et al. Iron Chelators and Alzheimer's Disease Clinical Trials. J Alzheimers Dis. 2024. ↩︎ ↩︎ ↩︎
Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular deferoxamine in patients with Alzheimer's disease. Lancet. 1991. ↩︎ ↩︎
Lannfelt L, Blennow K, Zetterberg H, et al. Safety and efficacy of PBT2 in Alzheimer's disease: a phase 2 randomised trial. Lancet Neurol. 2008. ↩︎ ↩︎ ↩︎
Mecocci P, Polidori MC. Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2012. ↩︎ ↩︎
Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB. Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr. 2008. ↩︎ ↩︎ ↩︎
Connor JR, Menzies SL, St Martin SM, Mufson EJ. A histochemical study of iron, transferrin, and ferritin in Alzheimer's disease brains. J Neurosci Res. 1992. ↩︎ ↩︎
Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997. ↩︎ ↩︎
Zheng W, Monnot AD. Regulation of brain iron and copper homeostasis by brain barrier systems. Pharmacol Ther. 2012. ↩︎ ↩︎
Honda K, Casadesus G, Petersen RB, Perry G, Smith MA. Oxidative stress and redox-active iron in Alzheimer's disease. Ann N Y Acad Sci. 2004. ↩︎ ↩︎