Pharmacological BACE1 inhibitor treatment during early progression of β-amyloid pathology maximizes therapeutic efficacy

Alzheimer’s disease (AD) is a chronic neurodegenerative disease of the central nervous system (CNS) characterized by progressive cognitive decline. AD is the most common cause of all dementia cases worldwide, and as a result of demographic aging the number of affected individuals grows at an alarming rate. The amyloid hypothesis of Alzheimer’s disease (AD) emphasizes amyloid-β peptide (Aβ) as primary cause of the disease, with toxic effects on synapses leading to cognitive decline and memory impairments. Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) as the rate-limiting enzyme of amyloidogenic processing of amyloid precursor protein (APP), is one of the prime drug targets for the treatment of AD. However, despite the development of potent and selective small-molecule BACE1 inhibitors, so far all human clinical trials have failed to rescue the cognitive decline in AD patients. Recent findings indicate that treatment has to be commenced before AD symptoms arise, since in symptomatic patients β amyloid deposition has already reached a plateau. Moreover, several studies have described dose-dependent adverse effects in animal models. Therefore, it is a central requirement to develop a treatment strategy that is therapeutically effective and at the same time avoids excessive interference with physiological function of BACE1. In this study, transgenic AD mice were treated at an early stage of β amyloid pathology with the potent, blood brain barrier penetrating BACE1 inhibitor NB-360. Longitudinal in vivo two-photon imaging was performed to repeatedly monitor individual amyloid plaques, presynaptic boutons and axonal dystrophies in living mice. In APPPS1 mice pharmacological BACE1 inhibition fails to revert but significantly reduces the progressive amyloid deposition and mitigates presynaptic pathology. Notably, the data show that plaque seed formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. These results imply, that preventive BACE1 inhibitor treatment is required to achieve therapeutic efficacy. For clinical therapy, to exploit the particular susceptibility of plaque formation to BACE1 inhibition, a dosage has to be empirically determined that effectively halts formation of new plaques rather than aiming at halting plaque growth. This strategy might optimally balance potential mechanism-based adverse effects and efficacious reduction of β amyloid deposition.Morbus Alzheimer ist eine chronische neurodegenerative Erkrankung des zentralen Nervensystems und äußert sich in progressivem Verlust kognitiver Funktionen und Gedächtnisleistung. Die Erkrankung ist die weltweit häufigste Ursache für Demenz und aufgrund demografischer Alterung in den Industrie¬ländern, nimmt die Zahl der Alzheimer Patienten stetig zu. Der Amyloid-Kaskaden-Hypothese zufolge, wird die Alzheimer Erkrankung durch pathologische Akkumulation und Aggregation des Aβ-Peptids (Aβ) ausgelöst. Aβ wird durch sequentielle enzymatische Spaltung des Amyloid-Vorläufer-proteins APP produziert. Die β-Sekretase BACE1 initiiert den ersten Schritt dieses sogenannten amyloiden Prozessierungswegs und ist somit eines der aussichtsreichsten Wirkstoffziele zur Senkung des Aβ-Spiegels. Im Verlauf der letzten Jahre wurden sehr wirksame und zugleich selektive BACE1 Inhibitoren hergestellt, doch bislang sind klinische Studien daran gescheitert, den progressiven Gedächtnisverlust aufzuhalten. Neueste Erkenntnisse weisen darauf hin, dass die Behandlung bereits vor dem Auftreten der ersten Symptome begonnen werden muss, da in symptomatischen Patienten die Ablagerung von Aβ in den meisten Fällen bereits abgeschlossen ist. Hinzu kommt, dass in den letzten Jahren vermehrt negative Begleiterscheinungen der Behandlung mit BACE1 Inhibitoren in Mäusen bekannt geworden sind. Die entscheidende Herausforderung ist somit, eine Behandlungsstrategie zu entwickeln, welche einerseits die physiologische Funktion von BACE1 nicht zu stark beeinträchtigt, aber zugleich therapeutische Effizienz gewährleistet. In der vorliegenden Studie wurden transgene Alzheimer Mäuse in einem frühen Stadium der β amyloiden Pathologie mit dem potenten BACE1 Inhibitor NB-360 behandelt. Mittels chronischer in vivo Mikroskopie konnten einzelne β amyloide Plaques, präsynaptische Boutons und axonale Dystrophien in lebenden Mäusen verfolgt werden. Die Behandlung erbrachte zwar keinen Rückgang der Aβ Ablagerung, konnte jedoch deren Fortschreiten verringern, sowie die progressive axonale Pathologie abschwächen. Insbesondere zeigten unsere Daten, dass die BACE1 Inhibitor Behandlung einen wesentlich größeren Einfluss auf die Bildung neuer β amyloider Plaques, als auf deren Wachstum hatte. Diese Ergebnisse weisen darauf hin, dass die Behandlung mit BACE1 Inhibitoren präventiv erfolgen muss. Für die klinische Anwendung könnte man sich die besondere Anfälligkeit der Neubildung von Plaques zu Nutze machen und über empirische Versuche einen Dosisbereich bestimmen, welcher ausreicht, die Neubildung von Plaques zu unterdrücken. Diese Strategie könnte zu einer ausgewogenen Behandlung führen, welche die progressive Aβ Ablagerung verzögert und gleichermaßen das Auftreten von Nebenwirkungen verhindert

Pharmacological BACE1 inhibitor treatment during early progression of β-amyloid pathology maximizes therapeutic efficacy

Alzheimer’s disease (AD) is a chronic neurodegenerative disease of the central nervous system (CNS) characterized by progressive cognitive decline. AD is the most common cause of all dementia cases worldwide, and as a result of demographic aging the number of affected individuals grows at an alarming rate. The amyloid hypothesis of Alzheimer’s disease (AD) emphasizes amyloid-β peptide (Aβ) as primary cause of the disease, with toxic effects on synapses leading to cognitive decline and memory impairments. Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) as the rate-limiting enzyme of amyloidogenic processing of amyloid precursor protein (APP), is one of the prime drug targets for the treatment of AD. However, despite the development of potent and selective small-molecule BACE1 inhibitors, so far all human clinical trials have failed to rescue the cognitive decline in AD patients. Recent findings indicate that treatment has to be commenced before AD symptoms arise, since in symptomatic patients β amyloid deposition has already reached a plateau. Moreover, several studies have described dose-dependent adverse effects in animal models. Therefore, it is a central requirement to develop a treatment strategy that is therapeutically effective and at the same time avoids excessive interference with physiological function of BACE1. In this study, transgenic AD mice were treated at an early stage of β amyloid pathology with the potent, blood brain barrier penetrating BACE1 inhibitor NB-360. Longitudinal in vivo two-photon imaging was performed to repeatedly monitor individual amyloid plaques, presynaptic boutons and axonal dystrophies in living mice. In APPPS1 mice pharmacological BACE1 inhibition fails to revert but significantly reduces the progressive amyloid deposition and mitigates presynaptic pathology. Notably, the data show that plaque seed formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. These results imply, that preventive BACE1 inhibitor treatment is required to achieve therapeutic efficacy. For clinical therapy, to exploit the particular susceptibility of plaque formation to BACE1 inhibition, a dosage has to be empirically determined that effectively halts formation of new plaques rather than aiming at halting plaque growth. This strategy might optimally balance potential mechanism-based adverse effects and efficacious reduction of β amyloid deposition.Morbus Alzheimer ist eine chronische neurodegenerative Erkrankung des zentralen Nervensystems und äußert sich in progressivem Verlust kognitiver Funktionen und Gedächtnisleistung. Die Erkrankung ist die weltweit häufigste Ursache für Demenz und aufgrund demografischer Alterung in den Industrie¬ländern, nimmt die Zahl der Alzheimer Patienten stetig zu. Der Amyloid-Kaskaden-Hypothese zufolge, wird die Alzheimer Erkrankung durch pathologische Akkumulation und Aggregation des Aβ-Peptids (Aβ) ausgelöst. Aβ wird durch sequentielle enzymatische Spaltung des Amyloid-Vorläufer-proteins APP produziert. Die β-Sekretase BACE1 initiiert den ersten Schritt dieses sogenannten amyloiden Prozessierungswegs und ist somit eines der aussichtsreichsten Wirkstoffziele zur Senkung des Aβ-Spiegels. Im Verlauf der letzten Jahre wurden sehr wirksame und zugleich selektive BACE1 Inhibitoren hergestellt, doch bislang sind klinische Studien daran gescheitert, den progressiven Gedächtnisverlust aufzuhalten. Neueste Erkenntnisse weisen darauf hin, dass die Behandlung bereits vor dem Auftreten der ersten Symptome begonnen werden muss, da in symptomatischen Patienten die Ablagerung von Aβ in den meisten Fällen bereits abgeschlossen ist. Hinzu kommt, dass in den letzten Jahren vermehrt negative Begleiterscheinungen der Behandlung mit BACE1 Inhibitoren in Mäusen bekannt geworden sind. Die entscheidende Herausforderung ist somit, eine Behandlungsstrategie zu entwickeln, welche einerseits die physiologische Funktion von BACE1 nicht zu stark beeinträchtigt, aber zugleich therapeutische Effizienz gewährleistet. In der vorliegenden Studie wurden transgene Alzheimer Mäuse in einem frühen Stadium der β amyloiden Pathologie mit dem potenten BACE1 Inhibitor NB-360 behandelt. Mittels chronischer in vivo Mikroskopie konnten einzelne β amyloide Plaques, präsynaptische Boutons und axonale Dystrophien in lebenden Mäusen verfolgt werden. Die Behandlung erbrachte zwar keinen Rückgang der Aβ Ablagerung, konnte jedoch deren Fortschreiten verringern, sowie die progressive axonale Pathologie abschwächen. Insbesondere zeigten unsere Daten, dass die BACE1 Inhibitor Behandlung einen wesentlich größeren Einfluss auf die Bildung neuer β amyloider Plaques, als auf deren Wachstum hatte. Diese Ergebnisse weisen darauf hin, dass die Behandlung mit BACE1 Inhibitoren präventiv erfolgen muss. Für die klinische Anwendung könnte man sich die besondere Anfälligkeit der Neubildung von Plaques zu Nutze machen und über empirische Versuche einen Dosisbereich bestimmen, welcher ausreicht, die Neubildung von Plaques zu unterdrücken. Diese Strategie könnte zu einer ausgewogenen Behandlung führen, welche die progressive Aβ Ablagerung verzögert und gleichermaßen das Auftreten von Nebenwirkungen verhindert

On the complementarity of pulsar timing and space laser interferometry for the individual detection of supermassive black hole binaries

Gravitational waves coming from Super Massive Black Hole Binaries (SMBHBs) are targeted by both Pulsar Timing Array (PTA) and Space Laser Interferometry (SLI). The possibility of a single SMBHB being tracked first by PTA, through inspiral, and later by SLI, up to merger and ring down, has been previously suggested. Although the bounding parameters are drawn by the current PTA or the upcoming Square Kilometer Array (SKA), and by the New Gravitational Observatory (NGO), derived from the Laser Interferometer Space Antenna (LISA), this paper also addresses sequential detection beyond specific project constraints. We consider PTA-SKA, which is sensitive from 10^(-9) to p x 10^(-7) Hz (p=4, 8), and SLI, which operates from s x 10^(-5) up to 1 Hz (s = 1, 3). A SMBHB in the range 2x 10^(8) - 2 x 10^(9) solar masses (the masses are normalised to a (1+z) factor, the red shift lying between z = 0.2 and z=1.5) moves from the PTA-SKA to the SLI band over a period ranging from two months to fifty years. By combining three Super Massive Black Hole (SMBH)-host relations with three accretion prescriptions, nine astrophysical scenarios are formed. They are then related to three levels of pulsar timing residuals (50, 5, 1 ns), generating twenty-seven cases. For residuals of 1 ns, sequential detection probability will never be better than 4.7 x 10^(-4) y^(-2) or 3.3 x 10^(-6) y^(-2) (per year to merger and per year of survey), according to the best and worst astrophysical scenarios, respectively; put differently this means one sequential detection every 46 or 550 years for an equivalent maximum time to merger and duration of the survey. The chances of sequential detection are further reduced by increasing values of the s parameter (they vanish for s = 10) and of the SLI noise, and by decreasing values of the remnant spin. REST OF THE ABSTRACT IN THE PDF FILE.Comment: To appear in the Astrophysical Journa

Gravitational waves from inspiralling compact binaries: Parameter estimation using second-post-Newtonian waveforms

The parameters of inspiralling compact binaries can be estimated using matched filtering of gravitational-waveform templates against the output of laser-interferometric gravitational-wave detectors. Using a recently calculated formula, accurate to second post-Newtonian (2PN) order [order $(v/c)^4$, where $v$ is the orbital velocity], for the frequency sweep ($dF/dt$) induced by gravitational radiation damping, we study the statistical errors in the determination of such source parameters as the ``chirp mass'' $\cal M$, reduced mass $\mu$, and spin parameters $\beta$ and $\sigma$ (related to spin-orbit and spin-spin effects, respectively). We find that previous results using template phasing accurate to 1.5PN order actually underestimated the errors in $\cal M$, $\mu$, and $\beta$. For two inspiralling neutron stars, the measurement errors increase by less than 16 percent.Comment: 14 pages, ReVTe

The gravitational wave background from star-massive black hole fly-bys

Stars on eccentric orbits around a massive black hole (MBH) emit bursts of gravitational waves (GWs) at periapse. Such events may be directly resolvable in the Galactic centre. However, if the star does not spiral in, the emitted GWs are not resolvable for extra-galactic MBHs, but constitute a source of background noise. We estimate the power spectrum of this extreme mass ratio burst background (EMBB) and compare it to the anticipated instrumental noise of the Laser Interferometer Space Antenna (LISA). To this end, we model the regions close to a MBH, accounting for mass-segregation, and for processes that limit the presence of stars close to the MBH, such as GW inspiral and hydrodynamical collisions between stars. We find that the EMBB is dominated by GW bursts from stellar mass black holes, and the magnitude of the noise spectrum (f S_GW)^{1/2} is at least a factor ~10 smaller than the instrumental noise. As an additional result of our analysis, we show that LISA is unlikely to detect relativistic bursts in the Galactic centre.Comment: Accepted for publication by MNRAS; New appendix on population of phase space in presence of gravitational wave inspira

Nearly horizon skimming orbits of Kerr black holes

An unusual set of orbits about extreme Kerr black holes resides at the Boyer-Lindquist radius $r = M$, the coordinate of the hole's event horizon. These ``horizon skimming'' orbits have the property that their angular momentum $L_z$ {\it increases} with inclination angle, opposite to the familiar behavior one encounters at larger radius. In this paper, I show that this behavior is characteristic of a larger family of orbits, the ``nearly horizon skimming'' (NHS) orbits. NHS orbits exist in the very strong field of any black hole with spin a\agt 0.952412M. Their unusual behavior is due to the locking of particle motion near the event horizon to the hole's spin, and is therefore a signature of the Kerr metric's extreme strong field. An observational hallmark of NHS orbits is that a small body spiraling into a Kerr black hole due to gravitational-wave emission will be driven into orbits of progressively smaller inclination angle, toward the equator. This is in contrast to the ``normal'' behavior. For circular orbits, the change in inclination is very small, and unlikely to be of observational importance. I argue that the change in inclination may be considerably larger when one considers the evolution of inclined eccentric orbits. If this proves correct, then the gravitational waves produced by evolution through the NHS regime may constitute a very interesting and important probe of the strong-field nature of rotating black holes.Comment: 9 pages, 5 figures, accepted for publication in PR

On Estimation of the Post-Newtonian Parameters in the Gravitational-Wave Emission of a Coalescing Binary

The effect of the recently obtained 2nd post-Newtonian corrections on the accuracy of estimation of parameters of the gravitational-wave signal from a coalescing binary is investigated. It is shown that addition of this correction degrades considerably the accuracy of determination of individual masses of the members of the binary. However the chirp mass and the time parameter in the signal is still determined to a very good accuracy. The possibility of estimation of effects of other theories of gravity is investigated. The performance of the Newtonian filter is investigated and it is compared with performance of post-Newtonian search templates introduced recently. It is shown that both search templates can extract accurately useful information about the binary.Comment: 34 pages, 118Kb, LATEX format, submitted to Phys. Rev.

Triplets of supermassive black holes: Astrophysics, Gravitational Waves and Detection

Supermassive black holes (SMBHs) found in the centers of many galaxies have been recognized to play a fundamental active role in the cosmological structure formation process. In hierarchical formation scenarios, SMBHs are expected to form binaries following the merger of their host galaxies. If these binaries do not coalesce before the merger with a third galaxy, the formation of a black hole triple system is possible. Numerical simulations of the dynamics of triples within galaxy cores exhibit phases of very high eccentricity (as high as $e \sim 0.99$). During these phases, intense bursts of gravitational radiation can be emitted at orbital periapsis. This produces a gravitational wave signal at frequencies substantially higher than the orbital frequency. The likelihood of detection of these bursts with pulsar timing and the Laser Interferometer Space Antenna ({\it LISA}) is estimated using several population models of SMBHs with masses $\gtrsim 10^7 {\rm M_\odot}$. Assuming a fraction of binaries $\ge 0.1$ in triple system, we find that few to few dozens of these bursts will produce residuals $>1$ ns, within the sensitivity range of forthcoming pulsar timing arrays (PTAs). However, most of such bursts will be washed out in the underlying confusion noise produced by all the other 'standard' SMBH binaries emitting in the same frequency window. A detailed data analysis study would be required to assess resolvability of such sources. Implementing a basic resolvability criterion, we find that the chance of catching a resolvable burst at a one nanosecond precision level is 2-50%, depending on the adopted SMBH evolution model. On the other hand, the probability of detecting bursts produced by massive binaries (masses \gtrsim 10^7\msun) with {\it LISA} is negligible.Comment: Accepted for publication by MNRAS, minor change