Introduction to Neurpathology [1] Flashcards
What is the significance of the rough endoplasmic reticulum (RER aka Nissl substance) and how it reacts to axotomy?
Nissl substance is organized stacks of rough endoplasmic reticulum and reflect active protein synthesis. When axons are transected, the Nissl substance disaggregates. v
What are the basic components of the neuronal cytoskeleton and how alterations of some of these components are associated with neurodegenerative diseases?
The neuronal cytoskeleton is comprised of longitudinally arranged neurofilaments, which are a type of intermediate filament 10nm long, and neurotubules which are 20-26nm long. Neurotubules are made of alpha and beta tubulin. These longitudinal fibers are cross linked and fastened by tau protein and microtubule associated proteins (MAPs). Tau and MAPs also anchor the cytoskeleton to the membrane and other organelles.
In Alzheimer’s Disease, abnormal paired helical filaments of hyperphosphorylated tau appear in the perikaryon (note: my understanding is that this is the cell body, distinct from the nucleus, of a neuron) and form neurofibrillary tangles (NFTs).
What are the uses of silver stains in the histological study of the CNS?
Visualizing axons and dendrites is best done with silver, which deposits on cytoskeletal elements that are dense in neuronal processes. The silver is black when viewed. There are several silver stains, the most common of which is Bielschowsky stain which shows normal axons and dendrites, as well as the NFTs of Alzheimers.
Know that GFAP is a key protein of astrocytes
GFAP makes up the intermediate filaments of astrocytes. GFAP is a component of Rosenthal fibers found in pathological processes. Rosenthal fibers are homogenous, eosinophilic, elongated or globular inclusions in the processes of astrocytes in the presence of long standing gliosis, tumors or metabolic disorders. Mutations of GFAP cause Alexander disease
How myelin is formed and what cells make myelin in the CNS and PNS?
Myelin production starts late in development, and begins in the periphery. This process continues after birth for many years. In the PNS, myelin is produced by Schwann cells, which can only ensheathe a single axon. The neurons induce Schwannc ell proliferation and migration along their axon length. Then, the Schwann cells enlongate and begin to ensheathe the axon. Last, the axons instruct the Schwann cells to begin wrapping them once the basal lamina is formed.
In the CNS, oligodendroglia are the myelin producing cells
What is the role of microglia in CNS inflammation and repair?
The microglia are the first line phagocytic cells of the brain. When resting, they sample the environment with their processes to sense foreign material, toxins and damaged tissue. When these cells find injury or invasion, they become activated, which causes their nucleus be enlarged and rod shaped with ramified cytoplasm. Also, they migrate to the site of the lesion, replicate and engulf foreign material or damaged neurons. Encircling degenerating neurons is known as neurophagia, while clustering around foci of necrotic brain tissue forms microglial nodules. Activated microglia secrete cytokines and neurotoxins that mediate neuroinflammation and can kill neurons. However, they also secrete trophic factors imperative in neuron repair.
What is the structure of the sarcolemma and key intracellular, transmembrane, and extracellular proteins associated with it, and how they are involved in the
pathogenesis of muscular dystrophies?
The sarcolemma is the cell membrane of the muscle cell. The sarcolemma invaginates deeply into the cytoplasm of the cell forming T-tubules. These tubules allow depolarizations of the membrane to rapidly penetrate the entire cell. The contractile myofibrils of muscle cell are attached to the sarcolemma and ECM by a series of proteins mainly composed of dystrophin, connecting the cytoskeleton to the membrane and dystrophin associated complex (DAC), made of transmembrane proteins. The DAC is made of five sarcoglycan protein subunits and 2 dystroglycan protein subunits. Dystroglycan is bound to merosin, part of the basement membrane
Describe how type I and type II fibers are distributed in normal muscle and in the denervation atrophy
Individual muscles are a mix of both types of fibers, but proportion can vary depending on the function of the muscle. However, there can be only one type of fiber per motor unit. It is the neuron that determines the type of muscle fiber.
What are the differences between central and peripheral myelin?
In both the CNS and the PNS, myelin is composed of about 70% lipid and 30% protein. The lipid is the same in both forms, a glycolipid called galactocerebroside, but proteins differ. In general, in the PNS, major myelin proteins are glycosylated, in the CNS, myelin proteins are not glycosylated
Describe the pathogenesis and pathological process of Wallerian degeneration and segmental demyelination. In which of these is recovery faster?
Wallerian degeneration occurs when an axon is transected and everything distal to the transaction degenerates. The soma swells, RER disintegrates, the nucleus displaces to the periphery of the cell and cytoplasm becomes smooth. Schwann cells distal to the transaction proliferate and provide a growing substrate for the axon. The amount of recovery depends heavily upon how well the cut axon ends are aligned and how much scarring is present.
Segmental demyelination is the result of dysfunction of the Schwann cell or damage to the myelin sheath. There is nothing inherently wrong with the axon. There is loss of myelin by breakdown in a few segments of the axon, causing a loss of salutatory conduction and reduces conduction velocity. Schwann cells can make new myelin to repair the damage, however; demyelination can lead to loss of axons and permanent damage.
What is Alexander disease?
Characterized by widespread deposition of Rosenthal fibers and clinically causes white matter degeneration and associated neurological dysfunction. Alexander is a slowly progressing, fatal disease of children that affects the myelin sheath and gives rise to dysfunction of white matter in the brain.
What are the key intracellular, transmembrane, and extracellular proteins associated with the sarcolemma
Dystrophin: Attaches contractile myofibrils of muscle to the sarcolemma and ECM. Connects the cytoskeleten to the membrane and dystrophin associated complex (DAC)
Sarcoglycan: Composes the DAC
Dystroglycan: Composes DAC. Bound to merosin, part of basement membrane
The DAC is made of 5 sarcoglycan and 2 dystroglycan subunits
How are the proteins of the sarcolemma involved in the
pathogenesis of muscular dystrophies?
Mutations in dystrophin give rise to Duchenne and Becker muscular dystrophy. Absence or abnormal expression of this protein causes ongoing degeneration and regeneration of muscle fibers. Degeneration is more rapid than regeneration and eventually the muscle fibers undergo necrosis. Muscle is replaced by fat and connective tissue, causing progressive weakness.
Mutations in the gene for DAC proteins can lead to limb girdle dystrophies and merosin mutations are found in some congenital dystrophies. Mechanism similar to above.
Astrocytes
Glial cells that are important in clearing neurotransmitters from the synaptic cleft, serving a structural support for blood vessels of the brain (part of the BBB), allowing neurons to migrate along them in the developing brain and in maintaining ionic equilibrium. When the brain is injured, the astrocyte is the major cell involved in scar formation: When an area of the brain is damaged the gap is closed by astrocyte hyperplasia and hypertrophy. A think network of astrocyte processes across the hole, but astrocytes are often incapable of filling the entirely of lesions.
Oligodendroglia
Myelin-synthesizing cells of the CNS. They may also have some nutritive role in the deeper layers of the cortex and basal ganglia. These cells have a very limited regenerative capacity and response to injury. If neurons lose myelin (as in a demyelinating disease such as MS), oligodendroglia attempt to remyelinate the fibers, but are often unsuccessful. Diseases such as MS can even cause death of oligodendroglia.
