Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Sajjad, Rabia; Arif, Rawaba; Shah, Amish A.; Manzoor, I.; Mustafa, Ghazala

doi:10.4172/pharmaceutical-sciences.1000397

Cited by 30 publications

(27 citation statements)

References 70 publications

(89 reference statements)

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“…Amyloid β peptide (Aβ) is a small (40 to 42 amino acids) proteolytic fragment of a glycosylated transmembrane protein, amyloid precursor protein (APP) . Accumulation of Aβ is a hallmark of Alzheimer's disease (AD) . Patient with AD is reported to have higher incidences of fractures and reduced bone mineral density (BMD), implying that there may be common pathogenic mechanism between AD and osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

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Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Yang

Chen

et al. 2020

FASEB j.

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Background Amyloid β peptide (Aβ) is involved in osteoporosis, but the effects of Aβ on osteoblast and bone formation remain unclear. In this study, we investigated the effect of Aβ on bone formation. Methods An animal model of osteoporosis was established by ovariectomy in C57BL/6 mice. The mice received intraperitoneal injection of Aβ. The effect of Aβ on the osteogenic differentiation of human bone marrow stromal stem cells (hBMSCs) and differentiation of both pre‐osteoblasts and pre‐osteoclasts in a co‐culture system were investigated. Results In the animal study, intraperitoneal injection of Aβ for 8 weeks promoted early and late osteogenic differentiation of hBMSCs. Aβ treatment significantly elevated osterix+ (osteoblastic) cells but decreased TRAP+ cells (osteoclasts) in the distal femur bone. In vitro study showed that Aβ treatment significantly enhanced matrix mineralization and osteogenic markers (Runx2 and osteocalcin). Aβ treatment activated Wnt/β‐catenin signaling in hBMSCs. The effect of Aβ was blocked by DKK1 (a Wnt/β‐catenin inhibitor) treatment. In the co‐culture system, Aβ treatment significantly increased the ALP activities of MC3T3‐E1 cells (pre‐osteoblasts) but reduced the TRAP+ RAW264.7 cells (pre‐osteoclasts). Aβ treatment upregulated TCF1 and OPG proteins in MC3T3‐E1 cells. Aβ treatment upregulated IκB‐α but downregulated NFATc1protein in RAW264.7 cells. These effects were blocked by XAV‐939 (a Wnt signaling antagonist), and then rescued by additional Wnt3a (a Wnt agonist). Conclusion Aβ treatment simultaneously promoted osteogenic differentiation via Wnt/β‐catenin signaling, and inhibited osteoclasts differentiation via the OPG/RANKL/RANK system, suggesting Aβ is a positive regulator of osteoblast differentiation and bone formation.

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Section: Introductionmentioning

confidence: 99%

“…6 Accumulation of Aβ is a hallmark of Alzheimer's disease (AD). 7 Patient with AD is reported to have higher incidences of fractures 8 and reduced bone mineral density (BMD), 9 implying that there may be common pathogenic mechanism between AD and osteoporosis. Nevertheless, the underlying mechanism remains not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Yang

Chen

et al. 2020

FASEB j.

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“…The most notable theory of AD development involves heightened accumulation of amyloid fragments due to altered APP processing, a transmembrane protein that is normally responsible for synaptic stability, neuronal protection, and neuronal growth [3][4][5]. APP has been known to have a positive effect on brain tissue via regulation of neurogenesis and neuronal proliferation [6][7][8], but when cleaved improperly it can give rise to Aβ which, in turn, can accumulate in excess and facilitate neuronal death [4].…”

Section: Senile Plaques and Neurofibrillary Tanglesmentioning

confidence: 99%

“…In an AD patient, the tau kinase/ phosphatase balance is impaired, with the balance being skewed towards tau kinases leading to hyperphosphorylated tau [2]. When tau is hyperphosphorylated, it assembles into tangles [3]. When the hyperphosphorylated form of tau is prominent, cellular processes that rely on tau are disrupted and axonal and dendritic transport are compromised.…”

Section: Senile Plaques and Neurofibrillary Tanglesmentioning

confidence: 99%

Microbial involvement in Alzheimer disease development and progression

Bulgart

Neczypor

Wold

et al. 2020

Mol Neurodegeneration

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Alzheimer disease (AD) is the most prominent form of dementia and the 5th leading cause of death in individuals over 65. AD is a complex disease stemming from genetic, environmental, and lifestyle factors. It is known that AD patients have increased levels of senile plaques, neurofibrillary tangles, and neuroinflammation; however, the mechanism(s) by which the plaques, tangles, and neuroinflammation manifest remain elusive. A recent hypothesis has emerged that resident bacterial populations contribute to the development and progression of AD by contributing to neuroinflammation, senile plaque formation, and potentially neurofibrillary tangle accumulation (Fig. 1). This review will highlight recent studies involved in elucidating microbial involvement in AD development and progression.

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“…The current prevailing theory, of which most medical research and development is predicated, is that Aβ deposition is the primary lesion that contributes to Alzheimer's disease and that neurofibrillary tangles are secondary, perhaps caused by the presence of Aβ. (Penke, Bogar, & Fulop, 2017;Sajjad, Arif, Shah, Manzoor, & Mustafa, 2018).…”

Section: Modern Descriptions Of Alzheimer's Disease (The 1900's-present)mentioning

confidence: 99%

Fostering compassionate care for persons with Alzheimer's disease in nursing facilities.

Cotton¹

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and her behaviors worsened, we were finally given a diagnosis: Alzheimer's disease. I did not know at the time the extent to which her diagnosis would impact me, the rest of my childhood, and how I learned to understand caregiving. From the onset of the disease to the final days, I watched as my mother took care of my grandmother day in and day out. My mother would work all day at her job, come home and make dinner for me, and then spend the rest of her evening taking care of my grandmother. Alzheimer's is not a disease that simply impacts the person, but the persons' family, friends, and communities but most importantly, it is the caregiver that is often impacted the most. These early experiences taught me that the caregiving journey could be difficult and arduous, so I want to acknowledge the work of caregivers for persons with Alzheimer's disease. In particular, I would like to say thank you to three caregivers that have taught me so much along the way-Margie, Zelda, and Doris. I would also like to thank my committee. Each of you has given me the support that I needed along the way. Annatjie, you are the MENTOR. I am not sure I would have made it without your help and encouragement. You are so brilliant and amazing, and I am v so thankful for all the guidance you have given me through this journey. Joseph, words cannot express how grateful I am for you! Thank you for encouraging me each step of the way. You are amazing! Pamela, your friendship and guidance is so helpful to me. Laughing (and sometimes crying) in the kitchen while eating too much fruit has saved me on many a day when I doubted my abilities to finish this dissertation. Terry, thank you for always checking in with me about my progress. Your feedback was so valuable to me. Dr. Jicha, when I first started to do research focused on Alzheimer's disease, it was your name that I kept seeing in the literature over and over again. You have done so much to advance this field of research, and I am so thankful that you said yes to being part of my committee. To my Institute for Sustainable Health & Optimal Aging family, your support while I was working on my dissertation was invaluable. Thanks for always cheering me on along the way. To my family and my friends, thanks for being my support system! Finally, to Bryce for all of his love and support. I would not have started this journey without your unwavering support. Thanks for buying the ticket and taking the ride.

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Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Cited by 30 publications

References 70 publications

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Microbial involvement in Alzheimer disease development and progression

Fostering compassionate care for persons with Alzheimer's disease in nursing facilities.

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