White matter tauopathy: Transient functional loss and novel myelin remodeling

Abstract

Early white matter (WM) changes are common in dementia and may contribute to functional decline. We here examine this phenomenon in an induced dementia model for the first time. We report a novel and selective form of myelin injury as the first manifestation of tauopathy in the adult central nervous system. Myelin pathology rapidly followed the induction of a P301 tau mutation associated with fronto-temporal dementia in humans (rTG4510 line). Damage involved focal disruption of the ad-axonal myelin lamella and internal oligodendrocyte tongue process, followed by myelin remodeling with features of re-myelination that included myelin thinning and internodal shortening. The evolution of the re-myelinated phenotype was complete in the molecular layer of the dentate gyrus after 1 month and in the optic nerve (ON) after 9 months of transgene induction and proceeded in the absence of actual demyelination, reactive glial changes or inflammatory response. The initial rapid myelin pathology was associated with loss of WM function and performance decline in a novel recognition test and both these effects largely reversed during the myelin re-modeling phase. The initial phase of myelin injury was accompanied by disruption of the vesicle population present in the axoplasm of hippocampal and ON axons. Axoplasmic vesicle release is significant for the regulation of myelin plasticity and disruption of this pathway may underlie the myelin damage and remodeling evoked by tauopathy. WM dysfunction early in tauopathy will disorder neural circuits, the current findings suggest this event may make a significant contribution to early clinical deficit in dementia.

Oligodendrogenesis increases in hippocampal grey and white matter prior to locomotor or memory impairment in an adult mouse model of tauopathy

“…Furthermore, when three human tauopathy MAPT variants are expressed under the control of the mouse α‐tubulin promoter, in the absence of endogenous Mapt , coiled bodies form inside spinal cord oligodendrocytes, and oligodendrocyte number is reduced by 6 months of age—prior to neuron loss (Higuchi et al, 2002). Consistent with these findings, the expression of MAPT P301L in CamKIIa + neurons was associated with thinner myelin ensheathing perforant pathway axons that project from the entorhinal cortex to the hippocampus (Jackson et al, 2018), and when expression of this variant was restricted to oligodendrocytes ( CNP promoter), myelin degeneration and axon loss from the spinal cord were detected prior to the development of tau aggregates in oligodendrocytes or oligodendrocyte loss (Higuchi et al, 2005).…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…Mouse models of tauopathy frequently demonstrate deficits in myelination, with evidence of filamentous tau inclusions developing in oligodendrocytes [149], resulting in defective myelination of the perforant path [117], spinal cord [149], and sciatic nerve [179]. Tauopathy-induced myelination deficits coincide with increased nerve conduction latency [117], cognitive decline [117], and motor impairments [179]. The mechanism by which tau pathology leads to deficits in myelination has yet to be fully elucidated, but there is evidence that this could represent a loss of normal tau function.…”

“…Coiled bodies of tau in oligodendrocytes and demyelination are also common features of other primary tauopathies such as PSP and CBD [ 291 ]. Mouse models of tauopathy frequently demonstrate deficits in myelination, with evidence of filamentous tau inclusions developing in oligodendrocytes [ 149 ], resulting in defective myelination of the perforant path [ 117 ], spinal cord [ 149 ], and sciatic nerve [ 179 ]. Tauopathy-induced myelination deficits coincide with increased nerve conduction latency [ 117 ], cognitive decline [ 117 ], and motor impairments [ 179 ].…”

Myelin lipids as nervous system energy reserves

“…In multiple sclerosis (MS), axon loss has been attributed to an energy failure 48 which could further drive demyelination. Many neuronal disorders, including Alzheimer’s disease, have been associated with hypometabolism 9 and white matter abnormalities 8,49,50 . Even psychiatric diseases have exhibit unexplained myelin abnormalities 51,52 .…”