The earliest stages of Alzheimer's disease are characterized by increasing aggregation of misfolded amyloid-β, but there is considerable debate over the role played by amyloid-β in the onset and progression of the condition. The failure of amyloid-clearing immunotherapies to improve patient outcomes has spurred a great deal of alternative theorizing, some of which regards amyloid-β aggregation as a side-effect of other, more important processes, and some of which adjusts the details by which amyloid-β produces pathology, but retains it as a central pillar of disease onset.
Unfortunately all animal models of Alzheimer's pathology are highly artificial, as the usual laboratory species do not naturally develop anything resembling the Alzheimer's neurodegenerative processes in humans. Thus the models reflect preconceptions about which processes are important. If a researcher thinks that a specific subset of amyloid-β aggregation is vital to the progression of Alzheimer's disease, then that lab will generate mice that exhibit this specific biochemistry. This strategy is inefficient, to say the least. The hypothesis leads to the mouse model, which leads to therapies that can rescue the mouse model, which leads to treatments that so far don't work well in humans, because the hypothesis is in some way incorrect.
It seems fairly well established that there is a dynamic equilibrium between amyloid-β in the brain and in the rest of the body. Researchers have run human trials based on attempts to clear amyloid-β in the bloodstream, and thus cause amyloid-β to leave the brain via the equilibrium mechanisms. This seems to be working modestly well so far, though it is only slowing progression of Alzheimer's disease. Amyloid-β is created in both the brain and the body, but which of these is the important source when it comes to the onset of Alzheimer's disease? In today's research materials, scientists suggest that Alzheimer's may originate in amyloid-β production in the liver. So of course they engineered a highly artificial mouse model in which that happens, producing neurodegeneration as a consequence. Sadly, this alone should give us little confidence that the liver amyloid hypothesis is a true reflection of what is going on in humans, for the reasons given above.
The concept is interesting, however, given recent work on the origins of α-synuclein aggregates in Parkinson's disease. It appears that in some fraction of Parkinson's patients, the α-synuclein responsible for the onset of the condition originates in the gut and then spreads to the brain. Given that, it isn't outrageous to suggest a bodily origin of the amyloid-β aggregation in Alzheimer's disease. It does, however, need more and better evidence in order to become convincing.
For several decades it has been generally accepted that Alzheimer's disease is caused by the accumulation of amyloid proteins in the brain. These proteins form toxic aggregations known as plaques and it is these plaques that damage the brain. Although doubts are growing regarding the veracity of the "amyloid hypothesis," the build up of these plaques is still the most prominent physiological sign of Alzheimer's. And one of the more interesting hypotheses going around suggests these damaging amyloid proteins originate in the liver.
The big challenge in investigating this liver-amyloid hypothesis is that amyloid is also produced in the brain. Most mouse models used in Alzheimer's research involve engineering the animals to overexpress amyloid production in the central nervous system, which only really resembles the minority of humans suffering from hereditary early-onset Alzheimer's. The vast majority of people developing the disease instead experience what is known as sporadic Alzheimer's, where the disease develops in older age, with no familial or genetic history.
The breakthrough in this new research is the development of a new animal model of Alzheimer's disease. Here, the researchers engineered a mouse to produce human amyloid proteins solely in the liver, and this allowed for novel observations into how these proteins can enter the bloodstream and travel to the brain. This new study offers clear evidence of a "blood-to-brain pathway." Using the newly developed mouse model the study shows how amyloid produced in the liver can move to the brain and cause damage leading to pathological signs similar to those seen with Alzheimer's disease.
Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.