The amyloid precursor protein (APP) is a transmembrane protein and the source of the amyloid beta-peptide that accumulates in plaques in the brain in Alzheimer's disease. However, the normal function(s) of APP are uncertain. In this episode I talk with Bassem Hassan, a developmental neurobiologist and molecular biologist at the Paris Brain Institute who has made major contributions that advance an understanding of the functions of specific genes in the processes of neurogenesis and the formation of neural networks. His research has provided evidence that APP normally functions in the regulation of brain development by influencing neuron progenitor cell proliferation and differentiation, and axon growth. These effects of APP on brain development involve facilitation of the well-known Wnt signaling pathway. Such findings suggest that genetic aberrancies that result in brain disorders such as Alzheimer's and Parkinson's may result from alterations in brain development that predispose to disease manifestation later in life.

LINKS

About Dr. Hassan:

https://parisbraininstitute.org/collaborators/hassan-bassem

Dr. Hassan's publications: https://scholar.google.com/citations?user=F8ExcEsAAAAJ&hl=en&oi=ao

Articles on APP function discussed in this podcast:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10275593/pdf/sciadv.add5002.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC8437438/pdf/elife-69199.pdf

https://journals.biologists.com/dev/article/141/13/2543/46288/Amyloid-precursor-protein-and-neural-development?guestAccessKey=

https://journals.physiology.org/doi/epdf/10.1152/physrev.1997.77.4.1081

There are about 100 billion neurons and 100 trillion synaptic connections between them in the human brain. The activity of those neural networks is controlled by only a handful of major neurotransmitters and all neurons respond to the excitatory transmitter glutamate and the inhibitory neurotransmitter GABA. This poses a major problem for using drugs that block or activate neurotransmitter receptors in understanding the function of specific circuits within and between brain regions and for treating neurological disorders. Ideally, the experimental neuroscientist wants to precisely control the activity of specific circuits of interest and the clinician wants to normalize the activity in dysfunctional circuits without altering the function of other circuits. Dr. Michael Tadross at Duke University has recently developed an ingenious solution to the problem of targeting selected neuron types with drugs – a technology called DART (drugs acutely targeted by tethering). In this episode Mike talks about his career path and how DART can be used to advance an understanding the function of specific neural circuits and may be used to restore brain function in disorders such as Parkinson's disease.

LINKS

Tadross laboratory: https://www.tadrosslab.com/tadross

Deconstructing behavioral neuropharmacology with cellular specificity: https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.aaj2161

DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity.: file:///Users/markmattson/Downloads/s41592-024-02292-9.pdf

Natural phasic inhibition of dopamine neurons signals cognitive rigidity: https://pmc.ncbi.nlm.nih.gov/articles/PMC11100816/pdf/nihpp-2024.05.09.593320v2.pdf

Distributed throughout the brain are oligodendrocyte precursor cells (OPCs) capable of proliferating and differentiating into the oligodendrocytes that wrap around axons (myelination) thereby greatly increasing signal propagation in neural networks. OPCs are essential for axon myelination during brain development, can enhance myelination in response to neural network activity, and can remyelinate axons in response to injury or in diseases such as multiple sclerosis. In this episode I talk with Johns Hopkins Professor Dwight Bergles about his career and work that is identifying the molecular pathways that regulate the proliferation and differentiation of OPCs, their integration into brain circuits and their roles in neuroplasticity in health in disease. During the past quarter century Dwight and his lab members and collaborators made several major discoveries that revealed previously unknown capabilities and functions of OPCs including that they receive synaptic inputs from glutamatergic neurons and respond to neuronal network activity locally and at a distance. And beyond their role in myelination very recent brain-wide cellular and molecular mapping studies suggest an even broader repertoire of OPC functions in the brain throughout life.

LINKS

Bergles Laboratory: https://bergleslab.com/

Oligodendrocyte Development and Plasticity.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4743079/pdf/cshperspect-GLI-a020453.pdf

Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus.

file:///Users/markmattson/Downloads/35012083.pdf

Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain.

https://pmc.ncbi.nlm.nih.gov/articles/PMC3807738/pdf/nihms-463905.pdf

Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury.

https://www.cell.com/action/showPdf?pii=S0092-8674%2826%2900112-1

Myelin is repaired by constitutive differentiation of oligodendrocyte progenitors.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12997438/pdf/nihms-2139155.pdf