Querol-Vilaseca M, Sirisi S, Molina-Porcel L, Molina B, Pegueroles J, Ferrer-Raventós P, Nuñez-Llaves R, Dols-Icardo O, Balasa M, Iulita MF, Blesa R, Belbin O, Clarimon J, Fortea J, Gelpi E, Sánchez-Valle R, Lleó A. Neuropathology of a patient with Alzheimer disease treated with low doses of verubecestat. Neuropathol Appl Neurobiol. 2022 Apr;48(3):e12781. Epub 2021 Dec 7 PubMed.
Recommends
Please login to recommend the paper.
Comments
Ludwig-Maximilians-Universität Munich
This is a careful and extensive characterization of the Aβ and synaptic pathology in an AD patient treated with a BACE inhibitor for 38 months at a low dose (12 mg of MK-8931/day). I am impressed that this single case does indeed reflect what we have seen in an amyloid AD mouse model threated with a BACE inhibitor (Peters et al., 2018 and 2019; Blume et al., 2018).
Most important is a reduced plaque size and reduced abundance of potential toxic Aβ species (NAB61 positivity) at dystrophic axons and synapses at plaques. This fits with our hypothesis that the effect of BACE inhibition is of great benefit at sites where BACE is accumulating in AD—which is within axonal dystrophies and presynaptic terminals at the border of fibrillary Aβ plaques.
This finding supports the idea that low-dose BACE inhibition following Aβ immunization removing fibrillary Aβ may halt synaptic loss due to the BACE accumulation and enhanced local Aβ production and aggregation within altered dystrophic axons and synapses.
References:
Peters F, Salihoglu H, Rodrigues E, Herzog E, Blume T, Filser S, Dorostkar M, Shimshek DR, Brose N, Neumann U, Herms J. BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathol. 2018 May;135(5):695-710. Epub 2018 Jan 11 PubMed.
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.
Blume T, Filser S, Jaworska A, Blain JF, Koenig G, Moschke K, Lichtenthaler SF, Herms J. BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines. Front Aging Neurosci. 2018;10:229. Epub 2018 Jul 26 PubMed.
University of Southampton, Faculty of Medicine
University of Southampton
Marta Querol-Vilaseca and colleagues report postmortem neuropathological findings in a patient with Alzheimer’s disease who had been treated with the BACE inhibitor Verubecestat until 15 months prior to death. Among their findings were no reduction in the amount of Aβ overall, but slightly smaller plaques and less of a subset of Aβ species associated with synapses compared with a group of untreated Alzheimer subjects. This seems consistent with β-secretase inhibition reducing the production of Aβ, but not affecting removal of Aβ that has already been deposited in plaques.
Quite correctly, the authors point out that on the basis of one case, it cannot be excluded that the findings are part of the inherent variability of AD and, in addition, the termination of treatment more than a year before neuropathological assessment may have influenced the findings.
However, the study highlights that although it is now possible to image amyloid, tau and inflammation in vivo by PET scans, there are subtleties of the Alzheimer pathophysiology that could only be detected by direct study of human brain tissue. How disappointing it is that, despite many thousands of patients with AD having participated in clinical trials of BACE inhibitors, immunotherapy, etc., insufficient priority has been given to systematic invitation for participants to donate their brains for study when their time comes. Such an endeavor could permit large enough groups for statistically powered studies to potentially detect effects of new treatments that are currently going undetected.
Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
In this paper, it's difficult to perceive a convincing difference in the verubecestat-treated case vs. the unrelated SAD “controls,” except for smaller, denser Aβ-IR plaques in the treated case. The NAB61/total Aβ density ratio as given in the paper is low in occipital but, tellingly, not in frontal cortex, because the denominator in the occipital cortex is unusually high (compare Figs. 1e and g). The authors couple this point with the apparent decrease in peri-plaque Syph+ neurites (Fig. 3 o, p).
However, other key measures of AD neuropathology—including tau, microglia, and astrocytes—show the Rx case to be essentially indistinguishable from the ASAD “controls.” And while the authors refer to NAB61-IR plaques as “a subset of fibrillar Aβ,” the literature indicates that NAB61 detects soluble oligomers of a wide range, not just a certain set of fibrils (Lee et al., 2006; Darocha-Souto et al., 2011).
The overall data are unpersuasive to me that there was a significant treatment effect on AD-relevant neuropathology. The authors appropriately mention the caveats that this is a comparison of a single treated case with a few SAD brains from an unrelated cohort, with small numbers and with no Rx in the last 15 months of the patient’s life.
A convincing effect of a BACE inhibitor on AD neuropathology would be a welcome finding, but the scattergraphs in Figs. 1 c-h and 2 c-g fall short of showing such a clear-cut effect. We need neuropathologic evaluation of many more autopsy cases from BACE inhibitor (and other) trials.
References:
Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem. 2006 Feb 17;281(7):4292-9. PubMed.
Darocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Serenó L, Rodríguez M, Sánchez B, Hyman BT, Gómez-Isla T. Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol. 2011 May;70(5):360-76. PubMed.
Make a Comment
To make a comment you must login or register.