PGC-1α Gene Therapy Slows Alzheimer's Progression in Mouse Model
It is always a good idea to look closely at the biochemistry involved in any potential Alzheimer's disease therapy that shows promise in mouse models. There is perhaps more uncertainty for Alzheimer's than most other age-related conditions when it comes to the degree to which the models are a useful representation of the disease state in humans - which might go some way towards explaining the promising failures that litter the field. In the research here, the authors are aiming to suppress a step in the generation of amyloid-β, one of the proteins that aggregates in growing amounts and is associated with brain cell death in Alzheimer's disease. They achieve this goal using gene therapy to increase the level of PGC-1α, which in turn reduces the level of an enzyme involved in the production of amyloid-β. Interestingly, increased levels of PGC-1α have in the past been shown to produce modest life extension in mice, along with some of the beneficial effects to health associated with calorie restriction.
Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying amyloid-β (Aβ) pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease.
Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
It would be interesting to see this gene being put under the control of a drug (e.g. Tetracycline) then activated when the mice models have early stage alzheimers.
Of course mice seem to be pretty rubbish models for human brain diseases. Are there any good non human primate models?
It would also be interesting to see Liz Parish of Bioviva offer this as a treatment. If it seemed to be successful in a few cases it could start to put some social pressure on the FDA.
More pcg1a means more telomerase and better mitochondrial function as shown by rando et al. P53, pcg1a aging axis. This gives some idea of what we get if we fix the damage upstream as the pcg1a pathway is critical to metabolism and stem cell mobility.
"It would also be interesting to see Liz Parish of Bioviva offer this as a treatment. If it seemed to be successful in a few cases it could start to put some social pressure on the FDA."
It would be interesting to see parrish produce any results worth a damn let alone her offering any kind of therapy. George church is doing things like this and is far more credible than a shady company like bioviva who have produced zero results worthy of note.
Axis of ageing: telomeres, p53 and mitochondria was by Dephino sorry. I mixed Dephino up with Rando for some reason, I blame being tired from flying and not arriving home till the small hours, no sleep and science = bad mix :)
https://www.ncbi.nlm.nih.gov/pubmed/22588366
One should always be suspicious of solutions for problems of aging involving modulation of metabolic pathways. In this case a previous study found that "PGC-1α overexpression exacerbates β-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease." I haven't dug into the two studies in any depth myself to parse out the differences that lead to the highly contrasting outcomes, but the authors of the study highlighted by today's FightAging! post note:
So, lest anyone start hunting around for drugs and supplements to generically pump up PGC-1α levels or activity ...