Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target

Abstract

The detection of myelin disruptions in Alzheimer's disease (AD)-affected brain raises the possibility that oligodendrocytes undergo pathophysiological assault over the protracted course of this neurodegenerative disease. Oligodendrocyte compromise arising from direct toxic effects imparted by pathological amyloid-␤ peptides and/or through signals derived from degenerating neurons could play an important role in the disease process. We previously demonstrated that 3؋Tg-AD mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant alterations in overall myelination patterns and oligodendrocyte status at time points preceding the appearance of amyloid and tau pathology. Herein, we demonstrate that A␤ 1-42 leads to increased caspase-3 expression and apoptotic cell death of both nondifferentiated and differentiated mouse oligodendrocyte precursor (mOP) cells in vitro. Through use of a recombinant adeno-associated virus serotype-2 (rAAV2) vector expressing an A␤ 1-42 -specific intracellular antibody (intrabody), oligodendrocyte and myelin marker expression, as well as myelin integrity, were restored in the vector-infused brain regions of 3؋Tg-AD mice. Overall, this work provides further insights into the impact of A␤ 1-42 -mediated toxicity on the temporal and spatial progression of subtle myelin disruption during the early presymptomatic stages of AD and may help to validate new therapeutic options designed to avert these early impairments.

Vascular burden and Alzheimer disease pathologic progression

“…23 Animal models have shown increased amyloid deposition after stroke, and white matter injury may predispose to the neurodegenerative effects of A␤. 9 Although the neurovascular hypotheses concerning A␤ clearance seem plausible, 24 little evidence from human studies suggests that vascular risks are also amyloidogenic. 25 Even though amyloid deposition can be enhanced by circulatory defects, vascular effects may be easily overwhelmed once AD pathology becomes advanced.…”

“…9 Brain microinfarcts may cause cognitive impairment via reduction of brain reserve, but the mechanism appears to be independent of typical AD lesions. 10 A recent study from the Alzheimer's Disease Neuroimaging Initiative (ADNI) has shown that the longitudinal changes in CSF A␤ 42 , [ 18 F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal volume are reflective of AD progression after cerebral amyloid deposition.…”

Amyloid precursor protein at node of Ranvier modulates nodal formation

“…38 Impaired myelinated axons have been detected in the brains of Alzheimer disease patients and been supposed as an early component of Alzheimer disease. [1][2][3]39,40 Abnormalities in CNS myelination affect the molecular organization at and around nodal axons leading to disturbances in CNS functions. For example, the heterozygous proteolipid protein transgenic mice exhibited profound reduction in Nav1.6 clusters, loss of the paranodal axo-glial apparatus, and a marked increase in Nav1.2.…”

Clinicotherapeutic Potential of Leptin in Alzheimer’s Disease and Parkinson’s Disease

“…Likewise, the vulnerability of oligodendrocytes to hypoperfusion, oxygen radicals, products of activated microglia, and other toxic insults or the alterations in cholesterol turnover and trafficking within the brain as a result of myelin injury and repair could be important determinants in AD pathology [77]. Similarly, A 42-induced caspase activation and apoptosis in mouse oligodendrocyte precursor cell line are crucial evidence linking myelin disruption with AD pathology [78]. The role of leptin in regulating myelin synthesis during brain development has been indicated in several studies over the years.…”