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/
"These findings indicate that exposure to fluoride, even at lower concentration, can aggravate the deficit in learning and memory and neuropathological lesions of the mice that express the high level of APP."

Cowburn RF, O'Neill C, Ravid R, Alafuzoff I, Winblad B, Fowler CJ - "Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer's disease" J Neurochem 58(4):1409-19 (1992) doi: 10.1111/j.1471-4159.1992.tb11357.x ... .tb11357.x

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
"A dose-response pattern of association was observed between mean fluoride levels and dementia in women (1.34, 95% CI 1.28-1.41, P < 0.001) and men (1.30, 95% CI 1.22-1.39, P < 0.001), with dementia risk more than doubled in the highest quartile compared with the lowest."

Zhang C, Ren C, Chen H, Geng R, Fan H, Zhao H, Guo K, Geng D - "The analog of Ginkgo biloba extract 761 is a protective factor of cognitive impairment induced by chronic fluorosis" Biol Trace Elem Res 153(1-3):229-36 (2013) doi: 10.1007/s12011-013-9645-4
"Ginkgo biloba extract EGb761 is widely used to treat patients with learning and memory impairment in Alzheimer's disease and Parkinson's disease in China. Our results suggest that EGb improved learning and memory in rats exposed to chronic fluoride, which was demonstrated in the Y-maze test."

Shi Y, Chen P, Sun A - "Effects of fluoride over-intake on the pathogenesis of Alzheimer’s disease and its cellular and molecular mechanisms" Chemistry of Life 10:2204-2214 (2021) [PFPC Library]


Jope RS, Song L, Li X, Powers R - "Impaired phosphoinositide hydrolysis in Alzheimer's disease brain" Neurobiol Aging 15(2):221-6 (1994) ... 8094901163

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

Ross BM, McLaughlin M, Roberts M, Milligan G, McCulloch J, Knowler JT - "Alterations in the activity of adenylate cyclase and high affinity GTPase in Alzheimer's disease" Brain Res 622(1-2):35-42 (1993) doi: 10.1016/0006-8993(93)90798-r

Scarpa M, Molloy C, Jenkins L, Strellis B, Budgett RF, Hesse S, Dwomoh L, Marsango S, Tejeda GS, Rossi M, Ahmed Z, Milligan G, Hudson BD, Tobin AB, Bradley SJ - "Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease" Proc Natl Acad Sci U S A. 118(50):e2107389118 (2021) doi: 10.1073/pnas.2107389118

GPR40 & Gq/11

Chen JJ, Gong YH, He L - "Role of GPR40 in pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia" J Drug Target 27(4):347-354 (2019) doi: 10.1080/1061186X.2018.1491979 ... 18.1491979
"In the presence of glucose, GPR40 was primarily activated by the Gq/11-phospholipase C (PLC) pathway."


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

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)

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) doi: 10.1192/bjp.150.5.674. PMID: 3651705.
"...there is evidence that TH regulates two of the main pathogenetic processes in AD, namely, tau protein phosphorylation [17] and the altered metabolism of amyloid precursor protein."

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)

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."

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."

Graebert KS, Lemansky P, Kehle T, Herzog V - "Localization and regulated release of Alzheimer amyloid precursor-like protein in thyrocytes" Lab Invest 72(5):513-23 (1995)

Graebert KS, Popp GM, Kehle T, Herzog V - "Regulated O-glycosylation of the Alzheimer beta-A4 amyloid precursor protein in thyrocytes" Eur J Cell Biol 66(1):39-46 (1995)

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)

Hayashi M, Patel AJ - "An interaction between thyroid hormone and nerve growth factor in the regulation of choline acetyltransferase activity in neuronal cultures, derived from the septal-diagonal band region of the embryonic rat brain" Brain Res 433(1):109-20 (1987)
"The observations indicate that subcortical cholinergic neurons, which are affected in Alzheimer's disease and in Down's syndrome, are subject to regulation by an interaction between thyroid hormone and local humoral factors such as NGF."

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/

Latasa MJ, Belandia B, Pascual A - "Thyroid hormones regulate beta-amyloid gene splicing and protein secretion in neuroblastoma cells" Endocrinology 139(6):2692-8 (1998)

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."

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."

Pietrzik CU, Hoffmann J, Stober K, Chen CY, Bauer C, Otero DA, Roch JM, Herzog V - "From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells" Proc Natl Acad Sci U S A 95(4):1770-5 (1998)
"In various species, thyrotropin (TSH) is known to stimulate both differentiation and proliferation of thyroid follicle cells. This cell type has also been shown to express members of the Alzheimer amyloid precursor (APP) protein family and to release the secretory N-terminal domain of APP (sAPP) in a TSH-dependent fashion."

Quinlan P, Horvath A, Eckerström C, Wallin A, Svensson J - "Altered thyroid hormone profile in patients with Alzheimer's disease" Psychoneuroendocrinology 121:104844 (2020) doi: 10.1016/j.psyneuen.2020.104844
"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."

Sampaolo S, Campos-Barros A, Mazziotti G, Carlomagno S, Sannino V, Amato G, Carella C, Di Iorio G - "Increased cerebrospinal fluid levels of 3,3',5'-triiodothyronine in patients with Alzheimer's disease" J Clin Endocrinol Metab 90(1):198-202 (2005) doi: 10.1210/jc.2004-1083
"Despite normal circulating thyroid hormone levels, AD subjects showed significantly increased rT(3) levels and an increased rT(3) to T(4) ratio in the face of unchanged CSF total T(4) and transthyretin levels. These results suggest an abnormal intracerebral thyroid hormone metabolism and possibly the occurrence of brain hypothyroidism, either as a secondary consequence of the ongoing process or as a cofactor in the progression of the disease."

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."

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."

Thomas DR, Hailwood R, Harris B, Williams PA, Scanlon MF, John R - "Thyroid status in senile dementia of the Alzheimer type (SDAT )" Acta Psychiatr Scand 76(2):158-63 (1987)
"When compared to controls, patients demonstrated a significantly lower free T3 value (but not free T4), a blunted TSH response to TRH, slightly elevated basal PRL and GH values and a small GH response to TRH"


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."

Link from old PFPC site:

TRH (TRH receptor is bound only to Gq/11)

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

Hsieh KP, Martin TF - "Thyrotropin-releasing hormone and gonadotropin-releasing hormone receptors activate phospholipase C by coupling to the guanosine triphosphate-binding proteins Gq and G11" Mol Endocrinol 6(10):1673-81 (1992)

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

Papers by Prof. Anna Strunecka, Charles University, Prague on aluminofluoride complexes - AlF(x)

Strunecka A, Blaylock RL, Strunecky O - "Fluoride, aluminum, and aluminofluoride complexes in pathogenesis of the autism spectrum disorders: A possible role of immunoexcitotoxicity" Journal of Applied Biomedicine 14(3):171-176 (2016)

Strunecka A, Blaylock R, Patocka J - "Aluminofluoride Complexes: Phosphate Analogues and a Hidden Hazard for Living Organisms"
Current Inorganic Chemistry 2(1):8-18(11) (2012) ... 1/art00003

Strunecká A, Patočka J - "Aluminofluoride Complexes in the Etiology of Alzheimer’s Disease" In: Roesky, H.W., Atwood, D.A. (eds) Group 13 Chemistry II. Structure and Bonding, vol 104 (2023) Springer, Berlin, Heidelberg.

Strunecka A, Blaylock RL, Patocka J, Strunecky O - "Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum" Surg Neurol Int 9:74 (2018) doi: 10.4103/sni.sni_407_17. Erratum in: Surg Neurol Int. 2018 May 08;9:98

Strunecka A, Strunecky O - "Chronic Fluoride Exposure and the Risk of Autism Spectrum Disorder" Int J Environ Res Public Health 16(18):3431 (2019) doi: 10.3390/ijerph16183431

Strunecká A, Strunecký O, Patocka J - "Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information" Physiol Res 51(6):557-64 (2002)

More on AlF(x):

Candura SM, Castoldi AF, Manzo L, Costa LG - "Interaction of aluminum ions with phosphoinositide metabolism in rat cerebral cortical membranes" Life Sci 49(17):1245-52 (1991). doi: 10.1016/0024-3205(91)90137-z. ... 059190137Z

Li L - "The biochemistry and physiology of metallic fluoride: action, mechanism, and implications" Crit Rev Oral Biol Med 14(2):100-14 (2003). doi: 10.1177/154411130301400204
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