Pathogenesis of cerebral amyloid angiopathy caused by chaotic glymphatics-Mini-review.

Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage in the elderly. It is also associated pathologically with Alzheimer's disease (AD). Both CAA and AD share similar pathology of deposition amyloid beta fibrils (Aß). Aß is deposited mainly in the neurites in AD and vascular walls in CAA. Aß is formed inside the brain parenchyma from the amyloid precursor protein. It is easier to understand how Aß is deposited in the cerebral neurites in AD. However, the pathogenesis of CAA is still largely unknown. It is difficult to understand or visualize how Aß fibrils formed inside the brain can be deposited against the cerebral perfusion pressure to be deposited in the cerebral and meningeal arterial walls. We encountered an unusual clinical case of acute aneurysmal subarachnoid hemorrhage which was followed after a few years with localized CAA involving mainly the sites of the subarachnoid hemorrhage. We reviewed the formation of Aß and postulated how the Aß fibrils are transported retrogradely toward the cerebral arteries and deposited in the arterial walls resulting in the final pathology of CAA. There is a clear disturbance of the glymphatic system, the aquaporin-4 channel, and the parenchymal border macrophages.

Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-α.

Amyloid-ß (Aß) is an intrinsically disordered peptide thought to play an important role in Alzheimer's disease (AD). It has been the target of most AD therapeutic efforts, which have repeatedly failed in clinical trials. A more predominant peptidic fragment, formed through alternative processing of the amyloid precursor protein, is the p3 peptide. p3 has received little attention, which is possibly due to the prevailing view in the AD field that it is "non-amyloidogenic." By probing the self-assembly of this peptide, we found that p3 aggregates to form oligomers and fibrils and, when compared with Aß, displays enhanced aggregation rates. Our findings highlight the solubilizing effect of the N-terminus of Aß and the favorable formation of structures formed through C-terminal hydrophobic peptide interfaces. Based on our findings, we suggest a reevaluation of the current therapeutic approaches targeting only the ß-secretase pathway of AD, given that the α- secretase pathway is also amyloidogenic.