. Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease. EMBO J. 2019 Dec 2;38(23):e102345. Epub 2019 Nov 7 PubMed.

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  1. This is an interesting finding that reveals further clues about the interplay between Aβ, BACE1, and tau. The use of in vivo two-photon imaging in APP/PS1 mice either with or without tau is a powerful technique that allows individual plaques to be tracked over time. Here, the authors show that plaque formation and progression is slowed down when tau is absent, and this may be linked to reduced peri-plaque BACE1 levels as these mice age. Their results suggest that BACE1 accumulation in dystrophic axons leads to increased Aβ generation, as our previous work has shown (Sadleir et al., 2016), thus exacerbating plaque formation and growth. It will be informative to expand these studies to other amyloid mouse models and to delve deeper into the mechanism of plaque reduction and how tau may be modulating BACE1.

    References:

    . Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):235-56. Epub 2016 Mar 18 PubMed.

  2. The study by Peters et al. using two-photon in vivo imaging to follow the kinetics of formation of Aβ deposits in an APPPS1 mouse model nicely demonstrates that deletion of tau in these mice (tau-/-.APPPS1) slows the growth of Aβ deposits and the formation of new ones during aging.

    This remarkable effect was associated with a reduction of BACE1 accumulation in plaque-associated dystrophic neurites in tau-/-.APPPS1 mice. BACE1 is a key enzyme in the generation of Aβ from APP. Its reported increase of levels in AD brain (Fukumoto et al., 2002; Holsinger et al., 2002; Tyler et al., 2002) and its accumulation in plaque-associated dystrophic neurites in AD and mouse models (Zhao et al., 2007) indicate it might play a role in local production of Aβ. Reduction of BACE1 in plaque-associated dystrophic neurites could thus be an interesting therapeutic approach, as pointed out by the authors.

    This study reinforces previous work demonstrating the beneficial effect of tau deletion on several behavioral and cellular deficits induced by amyloid pathology (Ittner and Götz, 2011; Morris et al., 2011; Leroy et al., 2012). We previously observed (Leroy et al., 2012) that tau deletion in another APPPS1 mouse model (5xFAD) had a beneficial effect on amyloid-associated deficits, i.e., reduced survival, memory deficits, loss of neurons, amyloid plaque burden, levels of Aβ, and increased levels of BACE1. These studies strikingly show that the interaction between Aβ and tau is not only unidirectional (e.g., as according to the amyloid-cascade hypothesis) but might well be bidirectional, at least in these experimental models, and that tau is needed for full development of amyloid pathology.

    Some differences between the observations of Peters et al. and ours are worth pointing out. 5xFAD mice have higher expression of BACE1 (Zhao et al., 2007), which was globally reduced after deletion of tau, whereas APPPS1 mice in the study of Peters et al. do not have increased BACE1 and it was reduced only in plaque-associated dystrophic neurites after tau deletion. In their 2-month-old APPPS1 tau-negative mice, Peters et al. did not find a reduction of soluble Aβ40 and Aβ42, whereas we found a reduction of both soluble and insoluble Aβ40 and Aβ42 in 6-month-old 5xFAD mice lacking tau, suggesting that tau deletion impaired β-secretase cleavage of APP in the 5xFAD model. Some of these differences might be explained by the different mice models used, i.e., APPPS1 versus 5xFAD and the different tau-/- mice (Dawson et al., 2001; Tucker et al., 2001), but also by age differences, since Peters et al. found that the formation of new plaques strongly declined only with aging after tau deletion and BACE1 levels increased with aging in 5xFAD mice (Zhao et al., 2007), suggesting that maximal beneficial effect of tau deletion on plaque formation occurs in more aged mice.

    The exact cellular mechanisms linking tau deletion and reduction of amyloid pathology in vivo are not yet completely deciphered. However, tau reduction prevents Aβ-induced defects in axonal transport (Vossel et al., 2010) that might be responsible for BACE1 accumulation in plaque-associated dystrophic neurites, and it blocks activation of GSK-3β (Vossel et al., 2015). Activation of GSK-3β was observed to be reduced in 5xFAD mice after tau deletion (Dawson et al., 2001). 

    The therapeutic consequences of tau deletion in AD might thus be twofold, preventing the formation of neurofibrillary tangles (e.g., by immunization or ASO/siRNA) and reducing the development of amyloid plaques. However, some caution should be taken when considering a tau-deletion approach, since chronic tau deletion in these genetic mouse models might cause cellular compensation effects that would not be present in acute tau deletion therapeutic paradigms in adulthood.

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    . Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol. 2002 Jun;51(6):783-6. PubMed.

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    . Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007 Apr 4;27(14):3639-49. PubMed.

    . Amyloid-β and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):65-72. PubMed.

    . The many faces of tau. Neuron. 2011 May 12;70(3):410-26. PubMed.

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    . Neurotrophins are required for nerve growth during development. Nat Neurosci. 2001 Jan;4(1):29-37. PubMed.

    . Lack of Tau Proteins Rescues Neuronal Cell Death and Decreases Amyloidogenic Processing of APP in APP/PS1 Mice. Am J Pathol. 2012 Dec;181(6):1928-40. PubMed.

    . Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010 Oct 8;330(6001):198. PubMed.

    . Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J Cell Biol. 2015 May 11;209(3):419-33. PubMed.

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