PubMed: 27671637

Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280.
Proceedings of the National Academy of Sciences of the United States of America
Anglada-Huguet M | Dennissen FJ | Mandelkow E | Mandelkow EM | Sydow A

Evidence 796b9423df

64627 treatment improved long-term object recognition memory in proaggregant Tau transgenic mice, as shown by increased novel object preference

Evidence e2147e06f9

ATP is reduced in the proaggregant transgenic slices, matching the lower mitochondrial density, compared with littermate controls or antiaggregant Tau transgenic slices (Fig. 3H)

Evidence fbbebcc476

Adenosine downmodulates neuronal activity (cFos levels), impairs the presynapse, and attenuates long-term potentiation (LTP) via the A1 receptor (21)

Evidence 8ddc8ded41

We also observed that Tau missorts into a subgroup of proximal dendrites, which correlates with a dramatic spine loss in the affected dendrites (Fig. S2 C and F)

Evidence 462c138f33

MC-1–positive Tau accumulates in the axonal grains of proaggregant Tau as described above (arrowheads), whereas antiaggregant slices remain unstained

Evidence b8ac31d252

In organotypic hippocampal slices, both proaggregant and antiaggregant Tau is missorted to the somatodendritic compartment as has been shown before (Fig. 1 A and B, asterisks)

Evidence c8a8857a5c

When corrected for the difference in total Tau, 12E8 phosphorylation does not differ between proaggregant and antiaggregant Tau (Fig. 2C)

Evidence f10d03c98c

The antibody AT180 (Tau pThr231) (18) shows (very) weak staining in the cell soma of both types of Tau transgenic slices (Fig. 2 G and H, asterisks) contrasting the high degree of Tau phosphorylated at Ser202/Thr205 [asterisks (somata) and long arrows (apical dendrites)] (AT8 antibody, Fig. 2 I and J)

Evidence cc02575fb0

The PHF-1 epitope (pSer396+pSer404, Fig. 2 D–F) is seen in both types of Tau transgenic slices where it appears in the somatodendritic compartment (asterisks) and in the axonal grains (arrowheads)

Evidence 466a435ee8

Only proaggregant Tau transgenic slices reveal Taupositive beaded structures in the neuropil oriented mostly perpendicular to the apical dendrites of the CA1 pyramidal cells (Fig. 1 C and D, arrowheads) resembling grains in human AGD (16)

Evidence 43c9e9ba0b

This suggests that proaggregant Tau accumulates in the axons as grains

Evidence cf2118bb42

Furthermore, we did not see colocalization of the grains of Tau and presynaptic marker synaptophysin (Fig. S3)

Evidence 33f6696b2c

In line with these observations, the presynaptic impairment in proaggregant Tau transgenic slices can be reversed by 64627 or BSc3094 without causing adverse effects in controls (Fig. 4F and Fig. S6)

Evidence 3e2a400ede

The axons of transfected neurons (Fig. 1 G and I) clearly reveal small inclusions of Tau (∼1 μm in size, arrowheads), although presynaptic boutons (e.g., giant mossy fiber boutons) are only marginally stained for Tau (Fig. 1I and Fig. S2 A and B; arrow), indicating that Tau does not accumulate at presynaptic boutons in these slices

Evidence 726207522b

Surprisingly, expression of neuronal activity marker cFos, astrocytic activity marker Gfap, and oxidative stress marker Hmox1 were reduced in the proaggregant Tau transgenic slices, whereas antiaggregant Tau transgenic slices were not different from littermate controls (Fig. 4A)

Evidence e576d29c02

64627 increases neuronal activity (Fos mRNA) both in proaggregant Tau transgenic slices and controls, although in case of the proaggregant slices neuronal activity is almost doubled, yielding levels similar to those of treated littermate control slices (Fig. 4D)

Evidence bd6cb603d5

Indeed, the reduced level of spines seen in proaggregant Tau transgenic slices are normalized when treated with 64627, whereas no significant changes are found in antiaggregant Tau transgenic slices or littermate controls (Fig. 5 A and B)

Evidence f17acc87e9

The axonal density of mitochondria, which is slightly lower in proaggregant compared with antiaggregant Tau transgenic slices, is marginally decreased by 64627 treatment albeit in a genotype-independent manner (Fig. S7)

Evidence 35324a385c

Surprisingly, the axonal grains of Tau appear to resist protein degradation because they are negative for markers of degradation (vimentin, ubiquitin, Lamp1, Sqstm1/P62, Hsc70, and Tia-1) (Fig. S5)

Evidence 7e4e50b9bd

Proaggregant Tau transgenic slices showed a significant reduction of spines compared with littermate control slices, whereas spine density of antiaggregant Tau transgenic slices was similar to controls (Fig. 3 A and B)

Evidence cffa87e85e

Mitochondria transport is similar in both kinds of Tau transgenic slices (Fig. 3E) with only a moderately lower mitochondrial density in proaggregant Tau transgenic slices compared with antiaggregant slices (Fig. 3F and Table S2)

Evidence 93f107af3b

We observed a typical paired-pulse facilitation (PPF) response in littermate controls and antiaggregant Tau transgenic slices, whereas in proaggregant Tau transgenic slices, the same stimulus paradigm resulted in a paired-pulse depression (Fig. 4B)

Evidence aab1c842dc

Having observed that 64627 restores presynaptic functioning (i.e., PPF, Fig. 4F), neuronal activity (induction of Fos, Fig. 4D), and dendritic spine levels in proaggregant Tau transgenic organotypic slices (Fig. 5 A and B), we tested whether we could restore long-term spatial memory in proaggregant Tau transgenic mice as well

Evidence 6d39c5f271

64627 reestablished novel arm preference in proaggregant mice, suggesting that 64627 restores spatial memory in these animals

Evidence 3e3e3e070a

This result suggests an impaired learning association between the sound and the foot shock in proaggregant mice, which can be rescued by 64627 treatment

Evidence 81d88d6828

Compared with untreated proaggregant Tau transgenic mice, treated mice (proaggregant Tau transgenics and littermate controls) have significantly larger maximal excitatory postsynaptic potential amplitudes (Fig. 5 G–I)

Evidence 6793cf2e2c

Treatment with 64627 increases the slope of the I/O curve in both proaggregant Tau transgenic slices and littermate controls (Fig. 5I).

Evidence 2deef30ef4

By contrast, dendrites that do not contain Tau are richly decorated with spines (>1 spines per μm), indicating that there is only local impairment of dendritic function in case of proaggregant Tau missorting

Evidence 2f39751200

We determined mitochondrial movements in live organotypic slices because aggregation-prone Tau is known to impair mitochondrial transport (Fig. 3 D and E)

Evidence 236054b27d

This suggests that the energy status of the neurons is compromised by proaggregant but not by antiaggregant Tau

Evidence 79011c874f

The slope of the input/output (I/O) curve is significantly reduced in proaggregant Tau transgenic mice compared with controls, indicative of impaired basal synaptic transmission (Fig. 5I)

Evidence 236cb8724c

Phosphorylation of these serines is known to induce detachment of Tau from microtubules and to promote missorting of Tau (17).


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