Peters F, Salihoglu H, Pratsch K, Herzog E, Pigoni M, Sgobio C, Lichtenthaler SF, Neumann U, Herms J. 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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Northwestern University Feinberg School of Medicine
Northwestern University
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:
Sadleir KR, Kandalepas PC, Buggia-Prévot V, Nicholson DA, Thinakaran G, Vassar R. 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.
Free University of Brussels, Faculty of Medicine
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.
References:
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002 Sep;59(9):1381-9. PubMed.
Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol. 2002 Jun;51(6):783-6. PubMed.
Tyler SJ, Dawbarn D, Wilcock GK, Allen SJ. alpha- and beta-secretase: profound changes in Alzheimer's disease. Biochem Biophys Res Commun. 2002 Dec 6;299(3):373-6. PubMed.
Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, Logan S, Maus E, Citron M, Berry R, Binder L, Vassar R. 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.
Ittner LM, Götz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):65-72. PubMed.
Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron. 2011 May 12;70(3):410-26. PubMed.
Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci. 2001 Mar;114(Pt 6):1179-87. PubMed.
Tucker KL, Meyer M, Barde YA. Neurotrophins are required for nerve growth during development. Nat Neurosci. 2001 Jan;4(1):29-37. PubMed.
Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M, Héraud C, Pierrot N, Yilmaz Z, Octave JN, Brion JP. 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.
Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010 Oct 8;330(6001):198. PubMed.
Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA, Ho K, Kim DH, Yu GQ, Mucke L. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J Cell Biol. 2015 May 11;209(3):419-33. PubMed.
Macquarie University
BACE inhibition as therapeutic strategy has experienced significant setbacks due to nonspecific inhibition of BACE2 as well as inhibition of tissue BACE1, both of which have resulted in significant adverse effects in human clinical trials. New hope to refine this therapeutics concept comes from this new study.
The study employs long-term monitoring of Aβ plaques in vivo using the APPPS1 transgenic mice with neuronal expression of human APP Swedish and human PSEN1. Finn Peters, Hazal Salihoglu et al. monitored plaques over a period of between 3 months and 6 months of age by two-photon imaging in the somatosensory cortex. When mice were crossed on tau-knockout background, the growth of plaques decelerated. Not only was the accretion rate of existing plaques lower in tau-/- APPPS1 mice, the rate of formation of plaques proximal to existing plaques—satellite plaques—was reduced, suggesting tau plays an active role in plaque generation once Aβ pathology has set in. Thus, tau appears to contribute to the deposition of amyloid plaques. This study extends results of plaque load in the absence of tau at single early time points (Roberson et al., 2007; Ittner et al., 2010).
Mechanistically, BACE1 seems to be at the heart of the matter. BACE1 activity surrounding plaques increases over time in AD brains and in mouse models such as APPPS1. APPPS1 tau-/- plaques show lower levels of BACE1 in their vicinity, yet tissue BACE1 levels are unaltered. This raises the intriguing thought that Aβ pathology induces a tau-dependent rise in BACE1 close to plaques, which enhances the existing pathology.
This work links tau with Aβ plaque deposition in a mechanistic way that suggests that targeting tau may indirectly ameliorate Aβ plaque pathology. Future work may address how this is linked to tau pathology.
For example, which forms of tau (soluble, monomeric vs oligomeric, modified/phosphorylated) contribute to BACE1 regulation proximal to plaques? Interestingly, in previous work, expression of pathogenic tau or human wild-type tau was shown to increase amyloid plaques (Jackson et al., 2016; Pooler et al., 2015). Furthermore, Aβ pathology in mice induces local perineuritic tau pathology (He et al., 2018).
Thus, the study by Peters et al. and other work consolidates therapeutic concepts that target both tau and Aβ to treat Alzheimer’s disease.
References:
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
Jackson RJ, Rudinskiy N, Herrmann AG, Croft S, Kim JM, Petrova V, Ramos-Rodriguez JJ, Pitstick R, Wegmann S, Garcia-Alloza M, Carlson GA, Hyman BT, Spires-Jones TL. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. Eur J Neurosci. 2016 Dec;44(12):3056-3066. Epub 2016 Nov 12 PubMed.
Pooler AM, Polydoro M, Maury EA, Nicholls SB, Reddy SM, Wegmann S, William C, Saqran L, Cagsal-Getkin O, Pitstick R, Beier DR, Carlson GA, Spires-Jones TL, Hyman BT. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathol Commun. 2015 Mar 24;3:14. PubMed.
He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, Zhang B, Gathagan RJ, Yue C, Dengler C, Stieber A, Nitla M, Coulter DA, Abel T, Brunden KR, Trojanowski JQ, Lee VM. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018 Jan;24(1):29-38. Epub 2017 Dec 4 PubMed.
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