Alzheimer's Disease as Laminopathy

The lack of tangible progress over the last fifteen years towards working therapies for Alzheimer's disease that are based on clearing amyloid has led to a great diversity of alternative thinking on the causes and pathology of the condition, as well as on other approaches to treatment. It is easier to theorize than it is to push therapies through trials, so this sort of thing is to be expected whenever the road ahead turns out to be much harder than expected. Some of the recent theorizing on Alzheimer's disease is quite promising, and some of it is quite dubious. From a first reading, this one falls somewhere in the middle. It should probably be read in the context of what has been discovered of the role of lamins in progeria versus in normal aging, the latter a work of investigation still very much in progress.

The cell nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo.

Neurons of tau transgenic Drosophila and of postmortem human Alzheimer's disease brains harbor significant invaginations of the nuclear envelope and have reduced levels of B-type lamin protein compared to controls. Dysfunction of B-type lamins has functional consequences in adult neurons in regard to heterochromatin formation, cell cycle activation, and neuronal survival. Taken together, our results suggest that pathological tau-induced stabilization of filamentous actin disrupts the LINC complex, which reduces lamin protein levels and causes the nuclear envelope to invaginate. Lamin reduction or dysfunction, in turn, causes constitutive heterochromatin to relax, allowing expression of genes that are normally silenced by heterochromatin and activating the cell cycle in postmitotic neurons, which causes their death.

Our findings suggest that Alzheimer's disease and associated tauopathies are, in fact, acquired neurodegenerative laminopathies. We demonstrate that loss of lamin function can lead directly to age-related neurodegeneration, indicating that basic mechanisms of aging are conserved between neurons and other somatic tissues. The lamin nucleoskeleton is thus a plausible molecular link between aging, the single most important risk factor for developing common neurodegenerative diseases, including Alzheimer's disease, and basic mechanisms of cellular senescence. Functional consequences of nucleoplasmic reticulum expansion in physiological aging and pathological conditions including cancer and Alzheimer's disease remain to be determined, however.

Link: http://dx.doi.org/10.1080/19491034.2016.1183859

Comments

Having just got back from seeing my mom (nearly 80 yrs old), after not seeing her for almost 3 years, it is heartbreaking to see her losing her memory. I am thankful society is pouring money in this terrible disease, much more than funds going into aging itself.

Watching Liz Parrish on a video, does anyone know when they will allow anyone to do medical tourism to one of their clinics and what is one of their first treatments (I assume clearing of Sencsient cells is one of them). I know that Liz treated herself a year or so ago. Also, any thoughts on the cost for this treatment? I may write to their web site with similar questions. Obviously, they would be the first to offer medical tourism treatments for anti-aging.

Posted by: Robert at May 19th, 2017 12:09 PM

If related to progeria, then perhaps several interventions may slow brain laminopathy, i.e. --

Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria.
https://linkinghub.elsevier.com/retrieve/pii/S1550-4131(12)00460-3

Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders
http://onlinelibrary.wiley.com/doi/10.1111/bcp.12928/full

A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds
(retinoids isotretinoin, tamibarotene and tazarotene, among other compounds were effective)
http://scholar.google.com/scholar_url?url=https%3A%2F%2Fwww.researchgate.net%2Fprofile%2FZhuyin_Li%2Fpublication%2F281540591_A_high-content_imaging-based_screening_pipeline_for_the_systematic_identification_of_anti-progeroid_compounds%2Flinks%2F570c41e908ae2eb94223bf8d.pdf&hl=en&sa=T&oi=gga&ct=gga&cd=0&ei=l90fWYbkFIqUmgHrhq3wAg&scisig=AAGBfm21qaRvsdSaTBNnfETB8s-KblZiug&nossl=1&ws=1124x801

All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745772/

Posted by: Lou Pagnucco at May 20th, 2017 1:29 AM

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