Alzheimer’s the tau hypothesis is proving to be just as controversial as amyloid beta,
Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
Front Neurosci. 2018; 12: 25.
Published online 2018 Jan 30. doi: 10.3389/fnins.2018.00025
According to this article
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The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.
Recent advances ( 11 years old ) in amyloid imaging have made it possible to observe Aβ amyloid accumulation in the patient's brain. As a result, it has been found that there are many normal patients with amyloid deposits, and also AD patients with very few amyloid deposits (Edison et al., 2007; Li et al., 2008).
It was previously reported that APP or APP fragments accumulated in dystrophic neurites in AD brains (Ishii et al., 1989) and that the accumulation of APP and its metabolic fragments induced neurotoxicity and vesicular trafficking impairment (Yoshikawa et al., 1992; Kametani et al., 2004; Roy et al., 2005). It has also been reported that synaptic disorders and dendritic dysplasia occur in the absence of Aβ amyloid deposition (Boncristiano et al., 2005), and that C-terminal fragments of APP cause synaptic failure and memory impairment (Tamayev et al., 2012). Furthermore, transgenic mice expressing the C-terminal intracellular domain of APP (AICD) developed Alzheimer's-like symptoms, such as accumulation of phosphorylated tau and memory impairment (Ghosal et al., 2009). Also, accumulation of APP C-terminal fragments triggers the hydrolysis of cAMP, causing impairment of the cAMP/PKA/CREB pathway (Kametani and Haga, 2015). Moreover, APP C-terminal fragment accumulation alters the subcellular localization of APP and the distribution of Rab11, and decreases endocytosis and soma-to-axon transcytosis of LDL (Woodruff et al., 2016), and this affects axonal vesicle trafficking (Szpankowski et al., 2012; Fu and Holzbaur, 2013; Gunawardena et al., 2013). These findings support the idea that APP C-terminal fragment accumulation causes neuronal impairment.
It was previously reported that APP or APP fragments accumulated in dystrophic neurites in AD brains (Ishii et al., 1989) and that the accumulation of APP and its metabolic fragments induced neurotoxicity and vesicular trafficking impairment (Yoshikawa et al., 1992; Kametani et al., 2004; Roy et al., 2005). It has also been reported that synaptic disorders and dendritic dysplasia occur in the absence of Aβ amyloid deposition (Boncristiano et al., 2005), and that C-terminal fragments of APP cause synaptic failure and memory impairment (Tamayev et al., 2012). Furthermore, transgenic mice expressing the C-terminal intracellular domain of APP (AICD) developed Alzheimer's-like symptoms, such as accumulation of phosphorylated tau and memory impairment (Ghosal et al., 2009). Also, accumulation of APP C-terminal fragments triggers the hydrolysis of cAMP, causing impairment of the cAMP/PKA/CREB pathway (Kametani and Haga, 2015). Moreover, APP C-terminal fragment accumulation alters the subcellular localization of APP and the distribution of Rab11, and decreases endocytosis and soma-to-axon transcytosis of LDL (Woodruff et al., 2016), and this affects axonal vesicle trafficking (Szpankowski et al., 2012; Fu and Holzbaur, 2013; Gunawardena et al., 2013). These findings support the idea that APP C-terminal fragment accumulation causes neuronal impairment.
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