With the advancement of medicine and health practices in the modern era, the average age of the population has increased. The healthcare system has continually been pushed to adapt in order to properly care for these elderly individuals and the health problems that arise with age. Advanced age in itself is one of the main risk factors for dementia, a perplexing class of neurological diseases. These devastating disorders place a large burden on families and the healthcare system in general. It is estimated that 47 million people are living with dementia worldwide, which carries an economic burden of almost $800 billion USD (WHO.int). These numbers are expected to grow along with the global population, which emphasizes the need to more deeply understand this pathology of memory loss.

Alzheimer Brain vs. helathy brain

Figure 1. Cross sections of the brain show atrophy, or shrinking, of brain tissue caused by Alzheimer’s disease (source: nia.nih.gov)

Alzheimer’s disease (AD) is the most common form of dementia in the world and contributes substantially to the above-mentioned statistics. Currently, AD remains an incurable condition despite a number of attempts at developing a therapy. The progressive loss of memory describes the general patient symptoms in AD while, at a cellular level, there is neuronal death and the deposition of two proteins, amyloid-β (Aβ) in extracellular plaques and tau in intracellular tangles, in the brain.There has been a great focus on these disease-associated protein hallmarks of AD in order to better understand their contributions to disease. A popular explanation for the progression of AD is the amyloid cascade hypothesis, where the misfolding of Aβ peptide initiates changes in the brain, leading to inflammation, intracellular tau tangles and neuronal death (Hardy and Selkoe). This framework for disease progression is supported  by studies showing that the earliest noticeable changes in early-stage AD involve perturbations in Aβ homeostasis, such as a decrease in a 42 amino acid species of Aβ in the cerebrospinal fluid (Bateman et al.). Based on these prevailing ideas within the field, Aβ has been targeted for therapeutics with the aim of preventing the initial changes that ultimately lead to memory loss.

Investigations into Aβ biology have been extensive since its discovery as the main component of amyloid plaques (Glenner and Wong; Masters et al.). The Aβ peptide is a cleavage product of the amyloid precursor protein (APP) with a length of 37-42 amino acids depending on the cut site (Bolduc et al.). The trigger for the amyloid cascade hypothesis is an increase in the amount of Aβ present in the brain either through mutations leading to the generation of pathogenic Aβ species from the APP protein or faulty protein clearance (Hardy and Selkoe). Following this slow accumulation of Aβ, stable “seeds” can form which then allow exponential aggregation of Aβ and the spreading of amyloid pathology through the brain similar to prion diseases, the classic protein-only disease (Jarrett and Lansbury; Eisenberg and Jucker; Jucker and Walker). This prion-like seeding phenomenon has been most convincingly demonstrated in mice expressing human APP that have accelerated deposition of Aβ throughout the brain after aggregated Aβ was injected into the hippocampus (Meyer-Luehmann et al.; Watts et al.; Morales et al.; Jucker and Walker; Rasmussen et al.). Astonishingly, different human APP transgenic mice (APP23 and APPPS1) also produce unique Aβ conformations that can then induce different Aβ pathologies (Meyer-Luehmann et al.; Heilbronner et al.). This emphasizes that Aβ is more than a simple by-product of disease but can induce prion-like spreading of amyloid deposits with remarkably distinct characteristics.


Figure 2. Aβ plaque pathology in the AD brain (a) spreads in a stereotypical pattern over time (b).   Adapted from Jucker and Walker.

Based on these previous studies, our group recently undertook a more extensive characterization of Aβ maturation within the two above mentioned mouse models, APP23 and APPPS1. Our goal was to determine how Aβ might change over the lifetime of the mice. Based on the average life span of the two mouse lines, 6 age groups were chosen and the brains of mice were compared in a variety of ways. Histology and biochemistry confirmed that Aβ levels increased over the lifetime of both lines. However, we were intrigued to find that the ratio of different Aβ species was not constant over time. Namely, the amount of Aβ42 (amino acid length) compared to Aβ40 (amino acid length) was increased in both mouse lines at the age of onset for Aβ deposition. We knew from studies in humans that Aβ42/40 is increased in patients with AD (Suzuki et al.; Scheuner et al.). In order to place this remarkable finding within a biological context, we injected brain extracts from these samples into the hippocampus of APP23 mice. All extracts generated from ages where Aβ deposition was detectable by histology, unsurprisingly induced deposition with the characteristic prion-like spreading we observed previously (Fig 3).

Abeta deposition

Figure 3. Aβ deposition is induced in the hippocampus by both APP23 (after 12 months) and APPPS1 (after 3 months) extracts. Scale bar=200μm. Adapted from Ye et al.

By serially diluting the brain extracts we were able to calculate the seeding dose 50 or SD50 (simply the dilution at which 50% of injected animals had induced Aβ deposition; similar to lethal dose 50). For both the APP23 and APPPS1 brain extracts, the SD50 plateaued with increasing age (Fig 2). Strikingly, when we considered the amount of Aβ in the extracts and calculated the specific activity (SD50/Aβ), there was a peak for both APP23 and APPPS1 extracts at the age when deposition was first detected (Fig 4). This suggests that the Aβ present in mice at this critical time point of deposition and, very likely the appearance of the first seeds, is unique in both biochemical and biological properties.

abeta deposition in mice

Figure 4. Total seeding dose 50 plateaus with increasing age while the specific activity peaks at the age of deposition in both mouse lines. Adapted from Ye et al.

We feel that this scientific finding, while interesting from a basic science perspective, also could have direct implications for AD in a clinical setting. While the hunt for a therapy targeting Aβ has been extensive, these efforts have largely failed to have a significant effect in human trials. Of note, it is widely accepted that changes in Aβ homeostasis occur decades prior to the onset of symptoms in AD (Bateman et al.; Ryman et al.). These disappointing clinical results could be explained by a failure to administer treatment early enough to stop the cascade of events leading to cognitive decline. Our results add another dimension to this argument by pointing to the fact that Aβ produced early in disease may be exceptional not only in the time it appears but also in its biochemical features and potency. We argue that it is crucial to intervene as early as possible in AD to have a chance at changing the course of this devastating disease. To implement these strategies, extremely sensitive biomarkers will need to be discovered in order to zoom in on this critical window.


Jay Rasmussen is a PhD  candidate in the Hertie Institute for Clinical Brain Research in the lab of Prof. Dr. Mathias Jucker in Tübingen, Germany.


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