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Apolipoprotein E leads to neuronal cell death in Alzheimer's disease


In neurodegenerative diseases, individual brain regions and certain neuronal cell types preferentially perish. For example, the neurons primarily affected in Parkinson's disease are located in particular in the aminergic nuclei of the brain stem, whereas in Alzheimer's patients the temporal lobe with hippocampus and entorhinal cortex is mostly affected.


By means of a precise molecular analysis of individual nerve cell types, Zalocusky and colleagues have now been able to work out the variability that appears to underlie the differences in disease susceptibility. In doing so, they identified a long-known protein that is increasingly expressed in degenerating nerve cells and plays an important role in neuronal cell death. The protein in question is apolipoprotein E4 (ApoE4).


There are three main forms of ApoE: ApoE2, ApoE3 and ApoE4. While the ApoE2 variant lowers the risk of Alzheimer's disease, people with one or two copies of the ApoE4 variant have a 3- and 14-fold higher risk of developing the disease, respectively. It is therefore not surprising that ApoE4 is the most important genetic risk factor for Alzheimer's disease. Although ApoE4 carriers make up only 20-25% of the general population, they account for 60-75% of Alzheimer's cases and develop the disease significantly earlier than people who do not have the ApoE4 allele.


ApoE is produced in the brain primarily by glial cells (astrocytes); however, in older age and neurological disease, it is also produced by neurons. Elevated levels of ApoE, found in about 20% of dying neurons in Alzheimer's patients, lead to cellular stress and activation of the immune system. As a result, the number of synaptic contacts decreases and neuroplasticity declines. Furthermore, tau pathology typical of Alzheimer's disease is enhanced.


In the 2021 paper published in Nature Neuroscience, mice have been genetically engineered to express a human ApoE4 variant. This is increasingly detectable in degenerating neurons. Thus, an increase in neuronal ApoE expression appears to be a predictor of neuronal cell death. Conversely, in animals unable to produce neuronal ApoE, the loss of neurons and synapses in the hippocampus is completely abolished. This important finding suggests that ApoE indeed plays a causal role in neuronal degeneration in the context of Alzheimer's disease.


In addition to intrinsic neuronal mechanisms, immune system involvement is further hypothesized, as Zalocusky et al. found that in both mice and human neurons, there was an upregulation of histocompatibility complex class I (MHC-I) in cells with high ApoE expression. The MHC-I pathway normally serves to display intracellular antigens on the cell surface, indicating to the immune system that the cell belongs to the body and should not be attacked. Alternatively, it could be attacked by a pathogen (e.g., a virus) and would need to be destroyed by specific immune cells.


Interestingly, MHC-I is elevated in dying neurons not only in Alzheimer's disease models but also in Parkinson's disease. ApoE-induced MHC-I overexpression could therefore be interpreted as an "eat me" signal to activate microglia and killer T cells, which then cause neuronal cell death.


Taken together, the present results suggest that neuronal ApoE regulates cellular stress and immune responses in healthy individuals as well as in Alzheimer's disease patients or people with milder cognitive impairment. Further deciphering the ApoE4-induced mechanisms leading to neuronal cell death may therefore provide important new targets for Alzheimer's disease therapy. It may be possible to use this knowledge to develop drugs to prevent or treat neurodegeneration by reducing neuronal expression of ApoE, disrupting the ApoE-MHC-I axis, or blocking induction of tau pathology.


References:


Wagner J, Neher JJ (2021) Killing aging neurons, one cell at a time. Nature Neuroscience 24:759


Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, Nelson MR, Rao A, Bennett DA, Bant J, Amornkul D-eJ, Xu Q, An A, Cisne-Thomson O, Huang Y (2021) Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease. Nature Neuroscience 24:786


Image credit: iStock/dra-schwartz

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