Alzheimer's Disease

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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Alzheimer's Disease

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Alzheimer's Disease
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A new study has reported that the neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID-19 patients (Reiken et al., 2022). The authors propose "that the alteration of cellular calcium dynamics due to leaky RyR2 in COVID-19 brains is associated with the activation of neuropathological pathways that are also found in the brains of AD patients."
"Future experiments will explore calcium channels as a potential therapeutic target for the neurological complications associated with COVID-19."
This is yet more evidence implicating Gq/11 proteins.

Gq/11 proteins are well-established to be the transducing G proteins for Ca(2+) mobilizing receptors and have been implicated in the pathophysiology of Alzheimer's Disease since the 1990s.

Activation of Gq/11 leads to initiation of the PLC/IP(3) pathway, thereby activating RyR, increasing intracellular calcium.

Gq/11 are the most important G-proteins stimulating phosphoinositide hydrolysis in the human brain (Pavia et al., 1998).

Fluoride poisoning may also produce identical neurological damage as is observed in AD. Fluoride poisoning is characterized by aberrant activation of G-protein-mediated pathways. Effects are bi-phasic, dependent on dose and duration, and are mediated mostly via thyroid hormone-regulated channels. Effects of fluoride on Gq/11 are well established.


Reiken S, Sittenfeld L, Dridi H, Liu Y, Liu X, Marks AR - "Alzheimer's-like signaling in brains of COVID-19 patients" Alzheimers Dement. 2022 Feb 3. doi: 10.1002/alz.12558. Epub ahead of print
https://alz-journals.onlinelibrary.wile ... /alz.12558


Cao K, Xiang J, Dong YT, Xu Y, Li Y, Song H, Zeng XX, Ran LY, Hong W, Guan ZZ - "Exposure to fluoride aggravates the impairment in learning and memory and neuropathological lesions in mice carrying the APP/PS1 double-transgenic mutation" Alzheimers Res Ther 11(1):35 (2019) ... MC6477877/

Goschorska M, Baranowska-Bosiacka I, Gutowska I, Metryka E, Skórka-Majewicz M, Chlubek D - "Role of Fluoride in the Etiopathogenesis of Alzheimer's Disease" Int J Mol Sci 19(12):3965 (2018) ... MC6320968/

Strunecká A, Patocka J - "Aluminofluoride complexes in the etiology of Alzheimer´s disease" In Structure and Bonding. New Developments in Biological Aluminum Chemistry; Atwood, D., Roesky, C., Eds.; Springer: Berlin/Heidelberg, Germany, 2003; pp. 139–181.

Russ TC, Killin LOJ, Hannah J, Batty GD, Deary IJ, Starr JM - "Aluminium and fluoride in drinking water in relation to later dementia risk" Br J Psychiatry 216(1):29-34 (2020) ... C91BE37B6D


Jope RS, Song L, Li X, Powers R - "Impaired phosphoinositide hydrolysis in Alzheimer's disease brain" Neurobiol Aging 15(2):221-6 (1994)

Jope RS, Song L, Powers R - "[3H]PtdIns hydrolysis in postmortem human brain membranes is mediated by the G-proteins Gq/11 and phospholipase C-beta" Biochem J 304 ( Pt 2):655-9 (1994)

Exton JH - "Role of G proteins in activation of phosphoinositide phospholipase C" Adv Second Messenger Phosphoprotein Res 28:65-72 (1993)

Kelly JF, Storie K, Skamra C, Bienias J, Beck T, Bennett DA - "Relationship between Alzheimer's disease clinical stage and Gq/11 in subcellular fractions of frontal cortex" J Neural Transm (Vienna) 112(8):1049-56 (2005) ... 004-0243-7

Kolasa K, Harrell LE, Parsons DS - "Effects of pertussis toxin and galpha-protein-specific antibodies on phosphoinositide hydrolysis in rat brain membranes after cholinergic denervation and hippocampal sympathetic ingrowth" Exp Neurol 161(2):724-32 (2000)

Ortiz-Capisano MC, Reddy M, Mendez M, Garvin JL, Beierwaltes WH - "Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor" Am J Physiol Renal Physiol 304(3):F248-56 (2013)

Pavía J, de Ceballos ML, Sanchez de la Cuesta F - "Alzheimer's disease: relationship between muscarinic cholinergic receptors, beta-amyloid and tau proteins" Fundam Clin Pharmacol 12(5):473-81 (1998) ... .tb00975.x


Accorroni A, Giorgi FS, Donzelli R, Lorenzini L, Prontera C, Saba A, Vergallo A, Tognoni G, Siciliano G, Baldacci F, Bonuccelli U, Clerico A, Zucchi R - "Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer's disease" Endocrine 55(3):981-984 (2017) doi: 10.1007/s12020-016-0897-6 ... 016-0897-6

Dolatshahi M, Salehipour A, Saghazadeh A, Sanjeari Moghaddam H, Aghamollaii V, Fotouhi A, Tafakhori A - "Thyroid hormone levels in Alzheimer disease: a systematic review and meta-analysis" Endocrine 79(2):252-272 (2023) doi: 10.1007/s12020-022-03190-w. Epub 2022 Sep 27. PMID: 36166162. ... 22-03190-w
(Low T3)

Karimi F, Borhani Haghighi A, Petramfar P - "Low levels of triiodothyronine in patients with Alzheimer's disease" Iran J Med Sci 6(4):322-3 (2011) ... MC3470275/

Quinlan P, Horvath A, Eckerström C, Wallin A, Svensson J. Altered thyroid hormone profile in patients with Alzheimer's disease. Psychoneuroendocrinology. 2020 Nov;121:104844. doi: 10.1016/j.psyneuen.2020.104844. Epub 2020 Aug 17. PMID: 32889491.
"Conclusions: Thyroid hormones were moderately altered in mild AD dementia with increased serum FT4, and in addition, the reduced T3/T4 ratios may suggest decreased peripheral conversion of T4 to T3. Furthermore, serum T3 levels were related to brain structures involved in AD development."

Belandia B, Latasa MJ, Villa A, Pascual A - "Thyroid hormone negatively regulates the transcriptional activity of the beta-amyloid precursor protein gene" J Biol Chem 273(46):30366-71 (1998)

Shabani S, Farbood Y, Mard SA, Sarkaki A, Ahangarpour A, Khorsandi L - "The regulation of pituitary-thyroid abnormalities by peripheral administration of levothyroxine increased brain-derived neurotrophic factor and reelin protein expression in an animal model of Alzheimer's disease" Can J Physiol Pharmacol (2018) 96(3):275-280. doi: 10.1139/cjpp-2016-0434. Epub 2017 Aug 28. PMID: 28846851.
"These findings indicated that L-T4 increased BDNF and reelin protein expression by regulation of serum THs and TSH level in Aβ-induced AD rats."

Ewins DL, Rossor MN, Butler J, Roques PK, Mullan MJ, McGregor AM - "Association between autoimmune thyroid disease and familial Alzheimer's disease" Clin Endocrinol (Oxf) 35(1):93-6 (1991)
"This study demonstrates a very high prevalence of autoimmune thyroid disease in Familial Alzheimer's Disease kindreds and suggests that a genetic factor contributing towards the development of autoimmune thyroid disease may be located on chromosome 21 within close proximity to the Familial Alzheimer's Disease gene."

Foster HD - "Disease family trees: the possible roles of iodine in goitre, cretinism, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases and cancers of the thyroid, nervous system and skin" Med Hypotheses 124(3):249-63 (1987)

Genovesi G, Paolini P, Marcellini L, Vernillo E, Salvati G, Polidori G,Ricciardi D, de Nuccio I, Re M - "Relationship between autoimmune thyroid disease and Alzheimer's disease" Panminerva Med 38(1):61-3 (1996)
"As compared to 30 non-demented controls, AD subjects showed a significant increase in the mean values of antithyroglobulin (TgAb) and antimicrosomial (MCSAb) autoantibodies."

Pico-Santiago G - "Alzheimer's disease: the untold story" P R Health Sci J 12(2):85-7 (1993)
"After considering the potential relationship between amyloid deposits and myxedematous infiltrations, the hypothesis is formulated that Alzheimer's disease may be due to functional hypothyroidism and may thus respond to thyroid therapy."

Molchan SE, Lawlor BA, Hill JL, Mellow AM, Davis CL, Martinez R, Sunderland T - "The TRH stimulation test in Alzheimer's disease and major depression: relationship to clinical and CSF measures" Biol Psychiatry 30(6):567-76 (1991)
"AD patients with a blunted TSH response had a significantly higher mean free T4 (FT4) level (p less than 0.03) and tended to be more severely demented than those with a nonblunted response."

Percy ME, Dalton AJ, Markovic VD, Crapper McLachlan DR, Gera E, Hummel JT, Rusk AC, Somerville MJ, Andrews DF, Walfish PG - "Autoimmune thyroiditis associated with mild "subclinical" hypothyroidism in adults with Down syndrome: a comparison of patients with and without manifestations of Alzheimer disease" Am J Med Genet 6(2):148-54 (1990)
"These data suggest that autoimmune thyroiditis associated with a mild "subclinical" form of hypothyroidism is common in adult DS patients and more pronounced in patients with AD manifestations than in those without. This "subclinical" hypothyroidism may contribute to cognitive deficits in ageing DS patients."

Sutherland MK, Wong L, Somerville MJ, Handley P, Yoong L, Bergeron C,McLachlan DR - "Reduction of thyroid hormone receptor c-ERB A alpha mRNA levels in the hippocampus of Alzheimer as compared to Huntington brain" Neurobiol Aging 13(2):301-12 (1992)
" Message levels for a thyroid hormone receptor highly expressed in brain (c-ERB A alpha) was reduced by 52% in CA1 and 43% in CA2 in Alzheimer hippocampus as compared to Huntington controls."


Labudova O, Cairns N, Koeck T, Kitzmueller E, Rink H, Lubec G - "Thyroid stimulating hormone-receptor overexpression in brain of patients with Down syndrome and Alzheimer's disease" Life Sci 64(12):1037-44 (1999)

Daimon CM, Chirdon P, Maudsley S, Martin B - "The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases" Am J Alzheimers Dis (Columbia) 1(1):10.7726/ajad.2013.1003 (2013) ... MC3817016/

van Osch LA, Hogervorst E, Combrinck M, Smith AD - "Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease" Neurology 62(11):1967-71 (2004)

Wang Y, Sheng Q, Hou X, Wang B, Zhao W, Yan S, Wang Y, Zhao S - "Thyrotropin and Alzheimer's Disease Risk in the Elderly: a Systematic Review and Meta-Analysis" Mol Neurobiol 53(2):1229-1236 (2016)

Christie JE, Whalley LJ, Bennie J, Dick H, Blackburn IM, Blackwood DH, Fink G - "Characteristic plasma hormone changes in Alzheimer's disease" Br J Psychiatry 150:674-81 (1987)
"...plasma TSH concentrations were higher throughout the day in Alzheimer-type dementia (ATD) than in age-matched depressed patients (MDD), and plasma TSH concentrations were also higher throughout the day in female ATD compared with age-matched female control subjects."


Daimon CM, Chirdon P, Maudsley S, Martin B - "The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases" Am J Alzheimers Dis (Columbia) 1(1):10.7726/ajad.2013.1003 (2013) doi: 10.7726/ajad.2013.1003

Other relevant literature

Rípová D, Platilová V, Strunecká A, Jirák R, Höschl C - "Alterations in calcium homeostasis as biological marker for mild Alzheimer's disease?" Physiol Res 53(4):449-52 (2004)

d'Uscio LV, Katusic ZS - "Vascular phenotype of amyloid precursor protein-deficient mice" Am J Physiol Heart Circ Physiol 316(6):H1297-H1308 (2019) doi: 10.1152/ajpheart.00539.2018 ... 00539.2018
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