Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

The article in 3 sentences.

There is an asymmetrical distribution of Abeta plaques deposition in the 5xFAD mouse model amongst brain regions closely related to memory, including the hippocampus and hippocampal-projected regions (medial prefrontal cortex, somatosensory cortex, medial amygdala, and thalamus).
The contradiction of Abeta deposition between this mouse model and AD patient samples—i.e the absence of Abeta deposition in the periaquiductal gray, olfactory nerve, substantia nigra, external capsule, central amygdala, hypothalamus—might represent an incomplete replicate of the human AD pathology.
The distribution of other pathological hallmarks of AD (e.g. neurofibrillary tangles, presenilin, apolipoprotein E) are future directions to enhance the translation from animal models to clinical applications.

I had thought that Abeta deposition would be evenly scattered across different brain regions in Alzheimer’s disease given its global impact on various cognitive domains. On the contrary, this study demonstrated the differential distribution of Abeta deposition in an AD mouse model. It would appear reasonable as short term memory impairments is one of the earliest signs of the disease. At the same time, what causes certain neurons to be susceptible to Abeta deposition, while others are left intact? What drives the specificity of such Abeta deposition? Do other unaffected neurons have protective mechanisms against Abeta? It would be interesting to decipher the molecular differences of neurons in different brain regions, as it seems that neurons within the same brain are not created equal.

Could Abeta deposition be related to the mitochondrial cascade hypothesis? It was found in this study that there was no detectable Abeta deposition in the hypothalamus of 5xFAD mice. This observation was contrary to the report of Abeta deposition in the paraventricular nucleus of the hypothalamus in autopsied AD human brains. The authors postulated that altered glucose metabolism may have contributed to the discrepancy, given the neuroendocrine system dysregulation in AD—where the hypothalamus is a part of. Similarly, the mitochondrial cascade hypothesis proposes that mitochondrial dysfunction is an intermediate step majority initiated by Abeta. The resulting abnormalities in energy production and glucose utilization would explain the subsequent neuronal death. Would the absence of Abeta in the hypothalamus of the 5xFAD mouse model suggest an alternative trigger event leading to mitochondrial dysfunction other than Abeta?