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Insulin Resistance as a Risk Factor for Alzheimer's Disease
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Carme Auladell, Jaume Folch, Antoni Camins
Although it is well known that insulin can modulate the phosphorylation of Tau protein, its role in the regulation of the insulin receptor has been also studied in recent years. Numerous studies have shown that, in addition to synaptic alterations, BIR is also involved in Tau hyperphosphorylation, through the inhibition of glycogen synthase kinase 3β (GSK3β) which exacerbates the development of LOAD. In accordance with this idea, mice that do not express insulin receptors at the neuronal level (NIRKO mice) as well as mice in which IRS-2 has been suppressed showed an increased phosphorylation of Tau through the inhibition of phosphoinositide 3 kinase (PI3K) / AKT signalling pathway (46, 83). This link between insulin and Tau signalling is mainly based on the modulation of downstream signalling pathways involving different kinases such as GSK-3β, JNK and AMP-activated protein kinase (AMPK) and phosphatases including protein phosphatase 1 and 2A (PP1and PP2A, respectively) (84). Surprisingly, Marciniak and colleagues reported that Tau deletion leads to the development of peripheral metabolic abnormalities observed in patients with LOAD, demonstrating a novel function of Tau protein in the control of BIR which contributes to cognitive and metabolic alterations in patients with LOAD and in tauopathies (85). Therefore, chronic BIR promotes the development of Tau pathology by altering the balance between kinases and phosphatases and vice versa.
Role of Vitamin D and Antioxidants in the Prevention and Treatment of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Shilia Jacob Kurian, Ruby Benson, Sonal Sekhar Miraj, Mahadev Rao
There are nine possible stereoisomeric forms of inositol present in nature. Myo-inositol (MI) is the most frequently available form in nature (Michell 2008). It has been reported that MI levels are elevated in the brain of patients with cognitive impairment and is suggested to be a marker for cognitive impairment and AD (Siger et al. 2009; Voevodskaya et al. 2016). Another isomer, scylloinositol that occurs in coconut, soursop, grapes, certain citrus fruits, etc., has been studied more in cognitive impairment and is considered to be a promising agent in patients with AD. In a mice model, scylloinositol showed improvement of the AD pathologies, neuroinflammation, and survival rate (Ma et al. 2012). In addition, it inhibits the β-amyloid-induced hyperphosphorylation of tau protein, and thereby reduces synaptic toxicity. Additionally, it inhibits the plasma binding of β-amyloid and regulates MI metabolism and phosphoinositol signaling in the brain (Jin and Selkoe 2015; Porsteinsson and Antonsdottir 2017).
Of brain and bone: The unusual case of Dr. A
Published in Howard J. Rosen, Robert W. Levenson, Neurocase, 2020
J. Narvid, M. L. Gorno-Tempini, A. Slavotinek, S. J. DeArmond, Y. H. Cha, B. L. Miller, K. Rankin
In summary, neuropathological investigations identified cerebral cortical atrophy in an asymmetric pattern, most convincingly in the frontal and temporal lobes. Numerous neurons elaborated tau protein, especially within the hippocampus and temporal lobe. Additionally, scattered tau positive astrocytes were found cerebral cortex and subcortical white matter. These patterns are most consistent with a diagnosis of Pick’s disease.
Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice
Published in Nutritional Neuroscience, 2023
Yasuhisa Ano, Yuta Takaichi, Rena Ohya, Kazuyuki Uchida, Hiroyuki Nakayama, Akihiko Takashima
Tau, a microtubule-associated protein, is primarily expressed in the central nervous system and is responsible for the polymerization and stabilization of microtubules. However, in the case of diseases, mutated and misfolded tau can form aggregates in non-native conformations. This contributes to both a reduction in the normal physiological activity of the tau protein and a toxicity-associated dysfunction. Tau aggregates known as neurofibrillary tangles contribute to dysfunction and degeneration in age-related neurodegenerative diseases[1]. Accumulating evidence shows that the deposition of phosphorylated tau induces inflammation and exacerbates neurological deficits, cognitive decline, and tauopathy[2–4]. Therefore, the phosphorylation and aggregation of tau represent critical therapeutic and preventive targets for dementia.
Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies
Published in Expert Opinion on Investigational Drugs, 2023
Francesco Panza, Vittorio Dibello, Rodolfo Sardone, Fabio Castellana, Roberta Zupo, Luisa Lampignano, Ilaria Bortone, Roberta Stallone, Nicoletta Cirillo, Christian Damiani, Mario Altamura, Antonello Bellomo, Antonio Daniele, Vincenzo Solfrizzi, Madia Lozupone
From a neuropathological point of view, tauopathies are characterized by insoluble aggregates of hyperphosphorylated tau protein, but the clinical spectrum of these conditions is various, complex and with partly overlapping presentations [5]. Currently, we recognize more than 26 different tauopathies [6], classified as primary and secondary/nonprimary tauopathies [7,8]. Primary tauopathies considered to be diseases are characterized by increased and abnormal tau aggregates as the primary underlying neurodegenerative process. However, some primary tauopathies may not have an accompanying clinical syndrome and could be considered age-related entities. Secondary/nonprimary tauopathies are characterized by a deposition of also another protein together with tau pathology. However, in secondary tauopathies, the role of tau pathology may not necessarily be downstream to this other protein-associated pathology [4], so recommending to use the term mixed tauopathies. The best known and studied secondary/mixed tauopathy is Alzheimer’s disease (AD) with amyloid-β (Aβ) depositions also present as a neuropathological hallmark in addition to abnormal tau deposition primarily manifesting as neurofibrillary tangles (NFT). Chronic traumatic encephalopathy (CTE) [9], subacute sclerosing panencephalitis [10], myotonic dystrophy [10], Lewy body disorders, Down’s syndrome [11], and Niemann-Pick disease-type C [11] are other secondary/mixed tauopathies.
The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies
Published in Expert Opinion on Drug Discovery, 2023
Madia Lozupone, Vittorio Dibello, Rodolfo Sardone, Fabio Castellana, Roberta Zupo, Luisa Lampignano, Ilaria Bortone, Roberta Stallone, Mario Altamura, Antonello Bellomo, Antonio Daniele, Vincenzo Solfrizzi, Francesco Panza
The principal neuropathological feature of tauopathies are hyperphosphorylated insoluble tau aggregates, with varying and almost overlapping clinical presentations, representing a complex spectrum of tauopathy-associated diseases and resulting clinical syndromes [5]. At present, among tauopathies, more than 26 different entities have been recognized [6], with a subclassification into primary and secondary or nonprimary tauopathies [7,8]. In primary tauopathies considered to be diseases, the primary underlying neurodegenerative process is the abnormal tau protein, although some primary tauopathies may be considered age-related processes, without a clinically defined presentation. In secondary or nonprimary tauopathies, deposition of tau protein may be associated with another protein. Therefore, in secondary tauopathies, tau pathology coexists with another type of pathology, although the pathological role for tau may be not necessarily downstream to this other pathology type [4], so suggesting that the term ‘mixed tauopathies’ should be preferable. Alzheimer’s disease (AD) is a secondary or mixed tauopathy in which, together with pathological tau deposition primarily manifesting as neurofibrillary tangles (NFT), amyloid-β (Aβ) is also present. Other secondary tauopathies are Lewy body disorders with also α-synuclein deposition, subacute sclerosing panencephalitis [9], myotonic dystrophy [9], chronic traumatic encephalopathy [10], Niemann-Pick disease-type C [11], and Down’s syndrome [11].