Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, affecting up to 1 in 20 individuals aged 65 and above. In addition to environmental and lifestyle factors, genetic mutations can predispose an individual to AD and some rare forms of inherited "familial" AD (fAD) are caused by known genetic mutations, with these affected individuals developing AD with high probability and at relatively young age. In most cases, AD is diagnosed at advanced stages, but pathological alterations in brain cells may arise earlier in life, particularly in fAD which is known to manifest earlier in life.
To study early-life changes in fAD brain cells, researchers including Zhen-Ge Luo and colleagues from ShanghaiTech University , China, have leveraged stem cell-derived brain organoids, to model aspects of early human brain development and function in the laboratory. Their work was published today in Stem Cell Reports. Organoids derived from fAD patients recapitulated AD-specific features such as increased amyloid protein, contained less mature neurons, and had higher cell death rates than healthy organoids. fAD organoids also had distinct changes in gene expression. One of the genes of note is TMSB4X which makes an anti-inflammatory protein called Thymosin β4 (Τβ4). Interestingly, like in the brain organoids, TMSB4X expression was also reduced in neurons of post-mortem AD patients brain samples.
Based on this discovery, the researchers treated fAD brain organoids with Τβ4 to test if this could prevent or reverse some of the AD-specific changes. Encouragingly, Τβ4 treatment reduced amyloid protein, increased the number of healthy neurons in the organoids and normalized gene expression changes. When given to mice with the fAD mutation it increased Τβ4 levels in the mouse brains, amyloid protein levels were reduced, and gene expression alterations were restored. Further Τβ4 reduced inflammation and prevented overactivation of neurons, a common feature in AD.
This study exemplifies how brain organoids can be used to identify potential AD-specific intervention targets. Further studies are required to confirm these findings and whether Τβ4 may be safe and effective for use in patients, if it has beneficial effects in patients already diagnosed with AD, and if it can delay disease onset in carriers of fAD mutations.
