Neurodegenerative disorders
May 16, 2017
Patogenesis?
 Inflammation
 Axon loss
 Metabolism
Electric and magnetic detection
of changes
 EEG
 Transcranial magnetic stimulation (TMS)
 Positron emission tomography (PET)
 Magnetic resonance imaging (MRI)
PET
Interneuronal
communication:
 Action potential („nothing
or everything“)
 Electric impuls along axon
 Cationic influx as a result of
pressure, voltage, light or
other neuron stimulation
 Excitation and inhibitory
synapses
 Threshold existance
 Characteristics of action
potential can be changed
Hematoencephalic barrier
 Is a barrier between blood and cerebrospinal fluid
 Dynamic process of molecular entry towards to CSF.
 Concentration of CSF proteins dependes on their origin
(blood or brain).
 Concentration of originally blood proteins is increasing
countinuously during their way from brain ventricles to
the spinal cord channel due to passive difusion.
 Movement energy of CSF is done by the differences
between arterial and venous system.
 When the barrier is not fuctionning well, blood protein
concentration is modulated by CSF flow; decreased CSF
flow increases entry of blood proteins
Insulin, glucose and brain
 Originally metabolism of glucose in brain
considered as insulin-insensitive
 Glial metabolism is insulin dependent
(insulin/IR).
 Brain can considered a tissue sensitive to
glucose and insulin.
 Common distribution of insulin, IR, GLUT1 and
GLUT4 in certain brain areas, especially in
hippocampus and plexus chorioideus.
CSF
 is generated by filtration of blood in the choroid plexus and
by diffusion from the extracellular matrix of the brain into
the ventricles.
 The CSF surrounds the brain and the spinal cord and there is
a constant diffusion of brain proteins into the CSF;
approximately 20% of the protein contents of the CSF are
estimated to be derived from the brain.
 CSF is produced at a rate of 500 ml/day and turns over
approximately 4 times per day by drainage into the blood;
thus, many ongoing processes in the CNS are reflected in
the protein composition of the CSF.
Insulin, glucose and brain
 Postprandial insulin levels maximally stimulate the
glucose metabolism in brain cortex, either directly
(similarly as in peripheral tissues), or indirectly by
pathway of insulin stimulated neuronal activation.
 Main transporter: GLUT1 in glial cells, partly sensitive to
insulin.
 Insulin possibly stimulates accumulation of glucose in
glial cells and its metabolisation on lactic acid for
neurons which had been stimulated by insulin.
Insulin, glucose and brain
 Insulin is also able to inhibit noradrenalin (NA)
uptake which activates glial NA βadrenoreceptors.
This is leading to release of
glucose from glycogen storage in glial cells.
 Any problems in cooperation of insulin and
glucose metabolism in neurons potentially
decrease ATP synthesis which is leading to
apoptosis.
Schematic of the hypothesized remote cell death mechanisms. After axotomy neuronal and glial
changes take place. Axonal lesion can trigger nitric oxide synthase synthesis and changes in the
expression of cannabinoid receptors with the appearance of the cannabinoid receptor type 2 in
neurons. Neurons that do not present these changes rapidly degenerate. Neuronal changes are
associated with both microglial and astrocytic activations. Selective activation of CB2 receptor is
associated with neuronal survival and inhibition of the reactive gliosis.
-Synuclein (SNCA)
 This presynaptic protein (140 AAs) is a main compound
of intracellular aggregates (Lewy´s bodies - PD).
 Three missence mutation identified in the gene SNCA
which is coding synuclein in patients with familiar
parkinsonism with a deficit of cognitive functions.
 Dynamics of synuclein in vivo depends on many
metabolic functions , especially related to proteasome
and lysosomal activities.
 Decrease of synuclein concentration in patients with
neurodegenerative diseases; exactly was not explained.
www-nature.com/scientific reports 5 :9506
DOI: 10.1038/srep09506
N-methyl D-aspartate) receptor
= a glutamate receptor, is the
predominant molecular device for controlling synaptic plasticity and
memory function.[
MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine)
is a neurotoxin that causes
permanent symptoms
of Parkinson's disease by
destroying dopaminergic
neurons in the substantia
nigra of the brain
PARP=Poly (ADP-ribose) polymerase
AIF = Apoptosis-Inducing Factor
Alzheimer's disease (AD)
 Alzheimer's disease (AD) is a progressive brain
amyloidosis that injures brain regions involved in
memory consolidation and other higher brain
functions.
 Neuropathologically, the disease is characterized
by accumulation of a 42 amino acid peptide
called amyloid β (Aβ42) in extracellular senile
plaques, intraneuronal inclusions of
hyperphosphorylated tau protein in neurofibrillary
tangles, and neuronal and axonal degeneration
and loss.
Alzheimer´s disease
 Cerebrovascular and neuronal dysfunction leading to
progressive loss of cognitive functions
 Tau protein and extracelular amyloid plaques whose
main compound is amyloid β (Aβ).
 Aβ (38–43 AK) is a side proteolytic product of amyloid
precurzor protein (APP).
 Oligomeric Aβ types (the smalest are dimers) are the
most synaptotoxic.
 The early onset of AD (<1%) is caused by mutations in
APP, presenilin 1 (PSEN1) or presenilin 2 (PSEN2) which
are leading to increased formation of APP.
Amyloid- -Peptides
 Amyloid-  (A  ) peptides with different lenght
are formed during enzymatic cleavage of 120
kDa transmembrane amyloid precursor protein
(APP) by 3 different secretases: -secretase
(BACE-1), -secretase and metalloproteinase
-secretase.
 The formed peptides have a different tendency
to aggregate according to their lenght and a
degree of posttranslational oxidation.
 Amyloid plaques in the brain of patients with
Alzheimer´s diseases (AD) are formed especially
by carboxyterminally prolonged forms of A
peptidase, as is A 1-42.
TACE=TNF converting enzyme
Neuroinflammation?
LRP=low-density lipoprotein receptor-related protein
Clearance Aβ can be realised
by several ways:
1 Transcytosis controlled by LRP
(purple, receptor) through
hematoencephalic barrier
(red, capillaries) removes Aβ
from CSF to blood. This
degradation of Aβ in smoth
muscle cells in blood vessels
and perivascularly decreases
Aβ also in exreacellular space
(blue, cells,
2 solubile LRP (purple, solubile
receptor) increases Aβ
clearance and decreases
levels of free Aβ in circulation
3 Aβ chaperones in CSF as
ApoE isoforms can reduce Aβ
clearance in dependence of
ApoE isoform (apoE4 > apoE3
and/or apoE2)
4 clearance Aβ by microglial
cells and perivascular brain
macrophages (orange, cells)
from brain parenchym and
perivascular spaces,
5 direct enzymatic Aβ
degradation in the brain
(green, enzymes),
6 elimination of Aβ from
perivascular spaces by a
passive drenage in
dependence on pulse arterial
flow
7 others?
Tau Protein
 Phosphoprotein tau (68 kDa) is a nativelly
unfolded protein related to microtubules. It is
responsible for microtubules stabilization.
 Affinity to microtubules is done by a different
phosphorylation state on 79 possible places.
 Neurofibrillary tangles are often found in
patients with AD. They are protein fillaments in
the form of stabile insoluble polymers of this tau
protein. The value of tau protein in CSF:
 In AD patients 300 - 900 pg/mL
 in Creutzfeldt-Jakob´s disease(CJD) - 1300
pg/mL
 More commonly as a marker for neuronal loss
ER – endoplasmic reticulum; GA – Golgiho aparát
neurofibrillary tangles
Sclerosis multiplex
 The most frequent inflammatory disease of
CNS
 Focal T cells, macrophage infiltrates,
demyelinization and axonal loss.
 Several forms
 CD4+ autoreactive T cells.
 HLA-DR15 haplotype in Caucasians
(DRB1 1501, DRB5 0101, DQA1 0102,
DQB1 0602) brings the strongest genetic risk.
Current understanding of the pathogenesis of MS and potential therapeutic targets.
Neuroinflammation has been classically described as the starting point in the pathology of MS.
Myelin-specific T cells are believed to orchestrate the autoimmune attack that leads to
oligodendrocyte damage and demyelination. Another hallmark of MS, however, is neuronal
damage involving both axonal and neuronal loss. Demyelination, axonal transection, and
neuronal loss are partly mediated by inflammation but might also occur independently of
inflammatory activity. This current understanding of MS pathology impacts directly on therapy
development. Ideally, patients need therapies that target both the process of inflammation and
the process of neurodegeneration.
Multiple sclerosis
Therapeutic potential of inhibitors of epigenetic processes in the treatment of multiple
sclerosis.
Epigenetic drugs such as histone deacetylase inhibitors, lysine acetyltransferase inhibitors
or DNA demethylating drugs have the capacity to rescue the distorted epigenetic
processes that affect the expression of genes in MS. In this way these drugs mediate
peripheral immunosuppressive activities either through skewing of dendritic cell function,
or directly by inhibiting the activities of Th1/Th17 cells or by promoting the activities of
Tregs. At the same time these drugs may also exhibit neuroprotective properties or
interfere in disease-associated pathogenic processes in astrocytes or microglia.
Multiple Sclerosis and Related Disorders
Volume 3, Issue 2, March 2014, Pages 163–175
Thank you for your attention