Alzheimer's disease represents a progressive neurodegenerative disorder associated with memory loss and cognitive impairment. Neuropathological hallmarks represent in particular senile plaques (SPs) containing fibrillar β-amyloid (Aβ40/42) and neurofibrillary tangles (NFTs). The latter result from increased phosphorylation of tau proteins, which are particularly detectable in the cortex and hippocampus of the temporal lobe.
Elimination of Aβ-amyloid from the brain is thought to slow the progression of Alzheimer's disease. This can be done via antibody therapy that binds Aβ precursors, but also via stimulation of glial cells that take up (phagocytose) Aβ. Although brain-derived microglia are known to play an important role in Aβ clearance, astrocytes are far more relevant numerically. Therefore, they are particularly suitable for the clearance of cerebral Aβ load.
Little is known to date about drugs that can be used to stimulate astrocytic Aβ clearance. Gemfibrozil (GFB) is a drug in the fibrate group used to treat dyslipidemia. This can be combined with retinoic acid (RA), a vitamin A derivative that regulates the expression of a variety of target genes. The combination of GFB and RA induces transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, at low doses and stimulates intracellular protein and organelle degradation.
Because lysosomes are critically involved in Aβ metabolism, a recently published study examined the effect of GFB-RA on Aβ uptake and degradation (Raha et al., 2021). The authors found that GFB-RA enters the brain after oral administration and upregulates lysosomal biogenesis and autophagy in mouse models of Alzheimer's disease. For this purpose, so-called 5xFAD mice were used, which multiply express human amyloid precursor protein and presenilin 1 in a mutant form.
The treatment resulted in a significant reduction of plaque burden and concomitantly in improved memory function and learning ability of the animals, without any drug-related side effects being observed. The molecular mechanism underlying this effect appears to be mediated by peroxisome proliferator-activated receptor α (PPARα), and the enhanced uptake of Aβ from the extracellular space occurred via an increase in low-density lipoprotein receptor (LDLR). Thus, increased lysosomal function may be a critical therapeutic mechanism for Aβ clearance.
PPARα is a transcription factor that regulates fatty acid degradation in the liver. Although fat is not degraded in the hippocampus, the authors of the above study demonstrated in previous work that PPARα is expressed in hippocampal neurons and in astrocytes. Therefore, GFB-RA-stimulated uptake of Aβ by astrocytes is the first step in this degradation process. Moreover, previous studies showed that overexpression of LDLR inhibits Aβ deposition and enhances clearance of extracellular Aβ. Furthermore, enhanced synthesis of TFEB leads to induction of lysosomal biogenesis and ultimately to enhanced uptake and clearance of Aβ.
In conclusion, GFB-RA stimulates astroglial uptake of Aβ via the PPARα-LDLR pathway and enhances Aβ degradation in astrocytes via the PPARα-TFEB pathway. Furthermore, orally ingested GFB-RA was demonstrated by Raha and colleagues to stimulate lysosomal biogenesis and autophagy, decrease plaque burden, and improve spatial memory and learning. It is therefore reasonable to assume that low-dose GFB-RA is useful as a treatment to reduce amyloid plaques and improve cognition in patients with Alzheimer's disease.
Reference:
Raha S, Ghosh A, Dutta D, Patel DR, Pahan K (2021) Activation of PPARalpha enhances astroglial uptake and degradation of beta-amyloid. Science Signaling 14:eabg4747.
Image credit: iStock/selvanegra
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