To Make New Neurons, Alzheimer’s-Affected Brains Need to do Some Cleaning

The Context: Alzheimer’s-affected brains do not make new neurons out of neural stem cells as efficiently as healthy brains, and this is an early sign of the disease. Brain cells in Alzheimer’s patients often also exhibit faulty mitochondria — the structures that give cells their energy.

The Study: A new study in Molecular Neurobiology by researchers at Weill Cornell Medicine, Columbia University, and Ludwig Maximilian University of Munich in collaboration with NYSCF Research Institute scientists finds that neural stem cells from Alzheimer’s patients are impaired in their ability to “trash” damaged mitochondria, potentially keeping them from turning into new neurons. 

The Importance: This study shows that the process of degrading damaged mitochondria could be a possible factor behind impaired neurogenesis in Alzheimer’s, giving scientists a new target for treatment development.

 A big problem with Alzheimer’s-affected brains is that they aren’t good at making new neurons. In the hippocampus — the brain structure associated with memory — new neurons are generated throughout your life, evolving from neural stem cells (NSCs). In an Alzheimer’s brain, however, neuron birth stagnates, and this is thought to factor into cognitive decline.

Another issue with Alzheimer’s-affected brains has to do with their mitochondria— the structures that give cells energy. Previous research has shown that mitochondria in the brains of Alzheimer’s patients can be malformed and inefficient. Cells have a way to clean up damaged mitochondria, a process called “mitophagy,” but if mitophagy doesn’t work correctly, cells can become weak and dysfunctional.

Could there be a link between sick mitochondria in NPCs and a lack of neurogenesis?

A new study in Molecular Neurobiology by researchers at Weill Cornell Medicine, Columbia University, and Ludwig Maximilian University of Munich in collaboration with NYSCF Research Institute scientists takes a closer look at cell regeneration in the brain and finds that Alzheimer’s-affected NPCs are impaired in mitophagy, potentially keeping NPCs from turning into new neurons.

What did the study involve?

The scientists first created NPCs from the stem cells of patients with a certain mutation that confers risk for familial Alzheimer’s disease (FAD) — a genetic form of Alzheimer’s that can sometimes appear as early as a patient’s 30s or 40s. Trouble with neurogenesis is a critical early sign of FAD, showing up often before the disease’s trademark plaques or neurodegeneration. The scientists also generated NPCs from healthy controls for comparison.

The team also found that NPCs from FAD patients displayed poorer mitophagy than healthy cells, and that certain proteins in charge of autophagy (the cell’s more general recycling system) were downregulated. With sick mitochondria and no way to get rid of them, these cells were then more likely to become depleted of energy, inefficient, and unable to become neurons.

What’s Next?

Now that researchers know impaired mitophagy affects neurogenesis, they can begin developing therapies which help NPCs better clear out damaged mitochondria, allowing the cells to survive and turn into new neurons. Such therapies would address an important component of Alzheimer’s and potentially help ameliorate some of the disease’s symptoms. 

Journal Article: 

Autophagy Induction by Bexarotene Promotes Mitophagy in Presenilin 1 Familial Alzheimer’s Disease iPSC-Derived Neural Stem Cells.
Martín-Maestro P, Sproul A, Martinez H, Paquet D, Gerges M, Noggle S, Starkov AA. Molecular Neurobiology. 2019. doi: 10.1007/s12035-019-01665-y.