Li X, Ospitalieri S, Robberechts T, Hofmann L, Schmid C, Upadhaya AR, Koper MJ, von Arnim CA, Kumar S, Willem M, Gnoth K, Ramakers M, Schymkowitz J, Rousseau F, Walter J, Ronisz A, Balakrishnan K, Thal DR. Seeding, maturation and propagation of amyloid β-peptide aggregates in Alzheimer’s disease. Brain, 2022, awac202 Brain
Recommends
Please login to recommend the paper.
Comments
Emory University
Xiaohang Li, Dietmar Thal, and their colleagues nicely demonstrate that the pathobiology of aggregating Aβ is an evolving process, changing as Alzheimer's disease progresses in different parts of the brain. Using an exogenous seeding paradigm, they find that the Aβ seeds that most potently stimulate deposition of the protein consist of post-translationally unmodified molecules that are the first to appear in the aging brain. Two post-translationally modified forms—N-terminal truncated/pyroglutamate-modified Aβ (AβN3pE) and phosphorylated Aβ (AβpSer8)—only emerge later in the cascade as components of mature Aβ plaques.
The authors note the implications of these findings for therapeutic approaches, i.e., later-stage deposits (and their sequelae) might most effectively be targeted by treatments that neutralize modified forms of Aβ, whereas different treatments could be needed to disarm the original, unmodified seeds.
Ideally, of course, the pathogenic properties of both modified and unmodified Aβ should be targeted, and the earlier in the course of this chronic disease, the better. The researchers mention the potential value of active immunotherapy, which could broadly engage relevant epitopes on aberrant assemblies of Aβ. I believe that, with just a few exceptions, the field too hastily abandoned active immunization as a primary prevention strategy for Alzheimer's disease.
The approach was (justifiably) hindered by vaccine-associated meningoencephalitis in some subjects with symptomatic AD (Orgogozo et al., 2003), a late disease stage when the brain is laden with Aβ-antigen. It would be worthwhile to determine whether immunization in younger subjects, before Aβ begins to accumulate in the brain, could safely and effectively delay or prevent AD.
Unfortunately, this is a tall order, given the time involved in prevention trials and uncertainty about long-term safety. We also lack an animal model of vaccine-induced meningoencephalitis that is predictive of the response in humans; such a model could speed the resolution of key issues.
Despite these impediments, active immunization is a path worth keeping open. Combined with tweaks to the delivery modality, adjuvant, and antigenic site(s) on Aβ, active immunization could become a simple, cost-effective, and widely available preventive measure for AD. Li and colleagues' findings support the view that a promising primary prevention target is the post-translationally unmodified Aβ seeds that are early drivers of the AD cascade.
References:
Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003 Jul 8;61(1):46-54. PubMed.
University of Goettingen
Li et al. have convincingly demonstrated that different forms of Aβ can trigger Aβ aggregation into amyloid plaques using human brain-derived amyloid preparations. They observed that full-length Aβ triggers early plaque development and spread, whereas N-truncated pyroglutamate Aβ3 or phosphorylated at Ser8 contribute to maturation of plaques. The authors speculate that “This may explain the lack of success when therapeutically targeting only specific forms of Aβ.“
From my point of view, it would have been interesting to also learn whether inoculation of diverse amyloid peptides derived from human brain into the brains of APP23 mice has a consequence on the well-being of mice. Are the induced plaques toxic, do they trigger neuron loss and memory deficits? This information would be be informative when considering what form of Aβ to target by active or passive immunization (reviewed in Bayer, 2022).
References:
Bayer TA. Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Mol Psychiatry. 2022 Apr;27(4):1880-1885. Epub 2021 Dec 8 PubMed.
Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
From en route to AAIC: This is a very cool paper overall. It’s not totally new, but I really enjoyed reading this work, and the findings makes sense to me.
Katholieke Universiteit Leuven, Department of Imaging and Pathology, Laboratory of Neuropathology
We are grateful for the comments on our recent manuscript.
We thank Dr. Walker for his statement about active vaccination as a potential strategy to overcome the problem that multiple species of Aβ can induce seeding and keep the process of Aβ accumulation and aggregation running.
Given that the vaccination-related meningoencephalitis was found in AD patients who already had Aβ deposits in the brain when vaccinated (Nicoll et al., 2003), it may be tempting to speculate that this “meningoencephalitis” represents just a very strong immune reaction against pre-existing vascular and cerebral Aβ, induced by the specific antibodies produced after exposition to the active vaccine. Accordingly, an active vaccination against Aβ accumulation may be a better option given prior to disease onset at younger ages. Research is definitely required to clarify this question in a proper manner, including the role of cerebral amyloid angiopathy in this matter.
Dr. Bayer’s question on the impact of the seeded plaques on the cognitive performance of the animals is very interesting. However, seeded Aβ plaques in Aβ-producing mice is probably not the best way to answer the general question behind Dr. Bayer’s specific question, i.e., the contribution of Aβ and its different types to neurodegeneration and cognition. The reasons are as follows:
(1) The host mouse line is prone to produce plaque pathology anyway and contains sufficient amounts of soluble Aβ forms to allow seeding. Thus, soluble Aβ may already have an impact on cognition in the mice as previously shown (Cleary et al., 2005).
(2) At the age of 6 months, APP23 mice show only a limited number of seed-induced Aβ plaques (Li et al., 2022). In humans, even higher Aβ loads are found in cognitively normal individuals (Arriagada et al., 1992; Thal et al., 2002). Therefore, we would not expect to see significant cognitive changes in mice after induction of seeding at 6 months.
(3) The stereotactic application of the seeds is a neurosurgical procedure that may theoretically by itself contribute to a mild reduction of cerebral performance, which cannot be excluded as a co-factor for cognition.
(4) In human AD, cognitive decline is mainly driven by abnormal tau (ptau) (Arriagada et al., 1992). In our study we used the occipital cortex, a brain region for producing lysates with seeds that accumulates tau pathology only in advanced stages of AD. Thus, we injected presumably ptau-free Aβ seeds when taking these samples from Braak stage IV AD cases. APP23 mice also do not develop spontaneous argyrophilic neurofibrillary pathology (Sturchler-Pierrat et al., 1997). Accordingly, the main AD-related driver for cognitive decline, i.e., fibrillar ptau, is lacking in APP-transgenic mice and the seeds.
Given all these points, plaque seeding is probably a less suitable model for determining the impact of plaque pathology on cognition. Moreover, amyloid PET follow-up studies have already shown an increase in Aβ pathology even in non-demented individuals (Hanseeuw et al., 2019), presumably indicating that spread of amyloid per se is insufficient to explain cognitive deficits.
Taken together, our recent finding that Aβ aggregation can be induced by any kind of Aβ plaques regardless of their biochemical composition and quantity raises the question whether active vaccines could induce a better clearance of all relevant pathological Aβ species than targeting only one specific form by way passive vaccination.
References:
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992 Mar;42(3 Pt 1):631-9. PubMed.
Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005 Jan;8(1):79-84. PubMed.
Hanseeuw BJ, Betensky RA, Jacobs HI, Schultz AP, Sepulcre J, Becker JA, Cosio DM, Farrell M, Quiroz YT, Mormino EC, Buckley RF, Papp KV, Amariglio RA, Dewachter I, Ivanoiu A, Huijbers W, Hedden T, Marshall GA, Chhatwal JP, Rentz DM, Sperling RA, Johnson K. Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurol. 2019 Jun 3; PubMed.
Li X, Ospitalieri S, Robberechts T, Hofmann L, Schmid C, Upadhaya AR, Koper MJ, von Arnim CA, Kumar S, Willem M, Gnoth K, Ramakers M, Schymkowitz J, Rousseau F, Walter J, Ronisz A, Balakrishnan K, Thal DR. Seeding, maturation and propagation of amyloid β-peptide aggregates in Alzheimer’s disease. Brain, 2022, awac202 Brain
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13287-92. PubMed.
Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.
Make a Comment
To make a comment you must login or register.