Seminars

• neurons

• glial cells

  • microglia

  • macroglia

    • astrocytes

    • oligodendrocytes

    • OPCs = NG2 cells = Polydendrocytes

    • ependymal cells

neurons

• 1x10^12

• specific network of synapses which governs all brain function

• only cell that performs the nervous system's actual function: information processing

• sports

• activity

all of them!

compromised —> some cells can flow through

= like “epithelial cells” between central canal and the ventricles

—> regulate composition and flux of the CSF

= immune cells

• first responder within minutes

• guardeners

• fast and proliferative

• second cells to respond —> creating a glial scar

• synaptic formation, stimulate axonal formation

• myelin debris clearance

• neurotransmitter recycling

—> myelinating of cells in CNS

<-> Schwann cells in PNS

special:

myelination of axons = 50:1 oligodendrocytes:Schwann cell

LNS and PDZ domain

= NG2 cells

functions:

• before birth: give rise to astrocytes and oligodendrocytes

• after birth: only give rise to oligodendrocytes

specialties:

• very proliferative

• can synapse with neurons and maintain synaptic contacts while proliferating (divide in halfs)

• act to damage

• in white and gray matter

• express transcription factor Olig2 and Sox10

• DO NOT express transcription factor GFAP

• binds to cytoskeleton via PDZ domain, Syntenin and ERM proteins

activated microglia

• IL-1 alpha

• TNF

• C1q

loss of normal function

• Synapse Regulation: inability to promote formation and function of synapses

  —> existing synapses are reduced and the formation of new synapses is inhibited

• Phagocytosis: inability to clear synaptosomes and toxic myelin debris

additionally

• Gain of Neurotoxicity

TGF beta

• inhibit A1

• block Il1 alpha, TNF, C1q

• reversion through TGF beta

Induction through activated microglia secreting IL-1α, TNF, and C1q

= combination necessary and sufficient

—> individual cytokines only trigger a partial phenotype

—> synergistic effect is essential to achieve the full functional transition and gene expression profile

Loss of function

• synapse regulation

  • existing synapses are reduced

  • formation of new synapses inhibited

• phagocytosis

  • synaptosomes and toxic myelin debris isn´t cleared out

—> inhibition of tissue repair and remyelination

• A primary challenge: selectively targeting the neurotoxic A1 phenotype

• A1 cells may serve good functions, such as fighting infections

yes

—> clusterin expression increased

—> inhibits differentiation of Oligodendrocytes and OPCs by inhibiting PI3K-AKT-mTOR pathway

—> loss of myelin production in CNS

• activating AKT (reduces damage of OPC´s)

• KO of astrocytic Clusterin (can restore OPC differentiation)

• B cells

  • autoantibodies against NG2 are targeting the surface of OPCs

• CD8 T cells

  • INF-gamma exposure induces MHC I expression on OPCs

  • direct cell damage through CD8

• reactive astrocytes express Clusterin

  • inhibition of the PI3K-AKT-mTOR pathway

  • changes in OPCs and Oligodendrocytes

• functions of the pathway

  • OPC proliferation, differentiation and cell survival

• inhibition by Clusterin

  • secreted Clusterin binds to (VLDLR) expressed on the surface of OPCs

  • reduction in the phosphorylation of PI3K, AKT, and mTOR

  • signals for survival and maturation of OPCs are turned off

  • + CLU prevents astrocytes from clearing myelin cell debris

—> cell death, no remyelination

• VLDLR (OPCs and mature oligodendrocytes)

• ApoER2 (astrocytes)

= most prevalent motor disease

—> affects the basal ganglia circuity

—> Striatum —> substantia nigra —> dopaminergic neurons

• no resting like heart —> need lots of energy, ATP

• full of iron

• resting tremor

• rigidity (“Zahnradphänomen” e.g. stern expression)

• bradykinesia (slow movements)

motor symptoms

BUT: begins before e.g. constipation, depression, bad sleep, neck/back pain

• L-Dopa —> symptomatic relief

  • works as a neurotransmitter

  • NO healing

• inserting brain pace maker in Nuc. subthalamicus

  • electric pulse

  • less able to judgements (go to prostitute, …)

  • Hinweis: Dopaminmangel führt dazu, dass N. subthalamicus dauerhaft überaktiv ist

• smoking

• coffee

= accumulation of alpha-Synucleine

= marker of cell death

• genetic mutations

• environmental toxins

• breakdown in cellular quality control

—> loss of dopaminergic neurons in the substantia nigra (pars compacta u. pars reticulata)

physiologically

mitochondria —> ATP production —> Neurons have a high demand on ATP

in Parkinson´s

—> impaired mitochondrial quality control

—> accumulation of dysfunctional mitochondria + increased oxidative stress

—> neuronal damage

mutations in

• PINK1 (PARK6)

• Parkin (PARK2)

= autosomal recessive juvenile Parkinson´s disease

PINK1 (PARK 6)

• senses mitochondrial damage

Parkin (PARK 2)

• labels damaged mitochondria for degradation

—> Mitophagy

= selective autophagic removal of damaged mitochondria

• damaged mitochondria: inability to import PINK1

• PINK1 accumulates on mitochondrial membrane

• PINK1 phosphorylates ubiquitin and activates Parkin

• Parkin ubiquitinates outer membrane proteins

• damaged mitochondria are degraded

mitochondrial dysfunction

• in autosomal recessive juvenile Parkinson´s disease

  • cause (PINK1 and Parkin mutations)

• in other forms of Parkinson´s disease

  • consequence of protein aggregation (α-Synuclein = Lewy-Körperchen)

• could promote apoptosis

• Parkin may degradade the survival protein Mcl-1, which accelerates the death of the nerve cell rather than protecting it

• compensatory mechanisms or the short lifespan

  • prevents mitochondrial damage from reaching the critical threshold for cell death

• different species respond very differently to the loss of PINK1 or Parkin

  • demonstrated by comparisons between resistant mice and more susceptible rats or fruit flies

—> release of mitochondrial DNA (mtDNA)

—> activation of innate immune pathways

cGAS-STING-pathway

• cytosolic DNA activates cGAS

• cGAS activates STING

• STING induces type I INF and inflammatory CKs

INF type 1 signaling increased

• Il-6

• TNF

• Il-1 beta

• INF beta

• promising strategy

  • complete loss in mouse models prevents the neurodegeneration

• complete blockade carries immunological risks

  • STING = key regulator of the innate immune response

  • results under germ-free laboratory conditions

  + it does not correct the original mitophagy defect

Parkin = responsible for clearing damaged mitochondria (Mitophagy)

Without Parkin

—> mitochondrial DNA (mtDNA) accumulates

—> triggers an immune response

motor function associated

demyelinating disease that concerns

• white AND grey matter

• cortical demyelination

periphery

—> Autoantigen not known

• sensory and visual disturbances

• motor impairments

• fatigue

• pain

• cognitive deficits

• gender

• age

• genetics (HLA)

• environment

• hygiene (more hygiene —> amount of prevalence)

• microbiome (dysbiotic?)

RR mice

—> develop EAE

• immunize with myelin antigen (autoantigen)

• transient autoimmune disease = EAE

• Experimental Autoimmune Encephalomyelitis

pathophysiology:

• CD4 pos T cells (autoantigen - MOG?) cross the blood brain barrier

• inflammation through microglia and macrophages

• northern hemisphere is more affected

• influence of the western diet

• (when McD came to Japan)

—> dysbiosis can lead to an increase of Th17 cells and an imbalance between Th17 and Treg —> blood with immune cells can flow through sinuses in the dura mater of the brain and get in touch with antigens of the CSF

• demyelination and axonal damage

  → progressive disability

• relapse-remitting (RRMS)

• progressive (PMS)

• gut-brain axis

• gut dysbiosis —> neuroinflammation and MS progression?

↓

• SCFA producing bacteria

• Faecalibacterium saccharivorans

• F. prausnitzii

↑

• Akkermansia —> phytate degradation is higher

• Ruthenibacterium lactatiformans

• H. hathewayi

• Eisenbergiella taya

shift away from SCFA-producing taxa

lower concentration of short-chain fatty acids (acetate, propionate)

—> can influence the T reg/Th17 ratio

—> can trigger inflammation

higher phytate degradation

• higher concentration of iron and zinc (usually binded by phytate) ↑

• higher concentration of myo-Inositol ↑

—> modulation of availability of minerals

DMT (Disease modifying therapy)

• e.g. Fingolimod (—> INF-beta)

• imbalance in bacterial species

  • decline in protective microbes e.g. Faecalibacterium prausnitzii (SCFA producing)

    • deficiency in immunoregulatory short-chain fatty acids and pyruvate

• functional metabolic changes promote inflammatory processes

• molecular mimicry of microbial peptides activates potentially autoreactive T cells.

• minimizes confounding factors such as

  • diet

  • lifestyle

  • geographic location

—> The study effectively reduces environmental variance while increasing statistical power to detect true MS-associated microbial and functional changes.

• basis for MS biomarkers

• future preventive or therapeutic strategies

  • development of “designer probiotics”

  • personalized therapy

—> genetic MS risk is the same

—> mostly same lifestyle and microbiome since they grew up in the same houshold

• T cell activation (ileal bacteria)

• molecular mimicry

  • bacterial antigens may cross-react with CNS autoantigen MOG triggeren T cell activation

• Treg suppression (ileal bacteria)

Th17 activation in CD4 before migration to CNS

• highest concentration of pro-inflammatory Th17 cells.

• disease-promoting bacteria could stay undetected in conventional stool samples

  • all enteroscopically collected samples differed from those in the fecal samples.

• alpha diversity = diversity within a single sample  

• beta diversity = comparison of microbial profiles between different samples

• no significant differences in either alpha or beta diversity

• BUT mice that developed MS-like disease showed distinct alpha and beta diversity compared to healthy recipients

• selective outgrowth of two Lachnospiraceae taxa

  • Lachnoclostridium

  • Eisenbergiella tayi

• reduction in alpha diversity and displaced other genera, such as Akkermansia (reduced)

  <-> gegensätzliche Erkenntnisse in den beiden papers

• Pia mater

• Arachnoidea mater

• superior sagittal sinus

• transverse sinus

—> in Dura mater

—> fenestrated, no blood-brain-barrier

—> antigens accumulate in immune hubs = neuroimmunological interfaces —> APCs meet antigens from CSF in dura mater —> efflux through lymphatic vessels into the dCLN

brain parenchyma —> soluble antigens can diffundate into CSF —> subarachnoid space —> cribiform plate —> afferent olfactory nerve rootlets —> nasal mucosa —> dCLN

BUT cells can´t actively leave through this way!

new research findings:

Brain parenchyma → Interstitial fluid/waste → Glymphatic system → CSF (generated in ventricles by choroid plexus) → Dural meninges → lymphatic vessels in Dura mater → deep Cervical lymph nodes (dCLN)

primed in the deep cervical lymph nodes

—> vascular system —> cerebral venous sinuses —> T cells and APCs can flow into the Dura mater and meet antigens from the CSF —> drainage through lymphatic vessels back into the cervical lymph nodes

• specialized immune centers or neuroimmunological interfaces

• NOT tertiary lymphoid structures

• the presence of organized stromal and immune elements is confirmed —> contribute to the maintenance of homeostasis

• The immune system is not “blind” to brain antigens but actively monitors them

  • through direct antigen presentation at the dural veins

• New T cells are not activated at the sinus hubs because there are hardly any naive T cells there

• only reactivate T cells that have already been activated

• Blocking lymphatic drainage therefore suppresses initial activation in the dCLNs rather than redirecting it

  —> imbalance between tolerance and autoimmunity

Thrombosis or inflammation could impair immune surveillance

evidenced by

• T-cell activation

• antigen accumulation (specfically e.g. amyloid-beta or MOG)

• cytokine release

• waste products from the brain are no longer properly removed

• toxic, misfolded proteins accumulate

• damaged or dead nerve cells

  —> may be a major cause of Alzheimer’s disease and other neurodegenerative disorders

= network along the blood vessels

• moves CSF through the brain tissue and flushes out cellular waste products

• waste products enter the CSF

• transported via the meningeal lymphatic network to the cervical lymph nodes

• Immune cells in the dura form a network

  • surveils the brain and maintains CNS homeostasis via cytokines

• dural sinuses are key hubs

  • they control T‑cell migration and allow CSF to enter the meningeal lymphatics for waste removal

—> elevated INF gamma production

—> damaged lymphatic endothelial cells through VE-Cadherin junction

—> lymphatic drainage impaired

—> waste is not transported to dCLN anymore

—> protein accumulation in the brain

No

• Only 3 % of the body mass

• 20 % of the total energy

• 10^11 (100 billion)

• 10^14

irreversible, progressive brain disease that slowly destroys memory and thinking skills

We don´t know

• amyloid plaques APP

• neurofibrilar tangles

= molecules

• “Tau-Protein”, phosphorylated, carry a negative charge

—> build plumps —> when it dissociates and falls apart —> neuron falls apart!

• 6 forms

• expressed in every cell type

• since birth

• First cut: β-secretase (BACE1) cuts APP outside the membrane.

• Second cut: γ-secretase cuts inside the membrane

1 hydrophile fragment (sAPPalpha) + P3 peptide —> cleaves —> safe!

e.g. ADAM10

“the only” ß-Secretase

—> cannot cleave at position 2 —> there must be a different enzyme!

—> Meprin ß

= alternative ß-Sekretase?

• differentially cleaves APP, but not in Swedish model

• mice model are 99% swedish mutation —> Meprin ß can´t be investigated

• soluble form of Aß

• NOT the plaques

Swedish/London mutation

—> in mice models: Swedish mutation

3 copies of APP-gene

A673T —> protects from Meprin ß cleavage

yes, but causes skin cancer

Aβ monomers –> Aβ-Oligomers –> Aβ-Protofibrils –> Aβ-Fibrils –> Aβ-Plaques

Aβ-Protofibrils = soluble = neurotoxic

ApoE4

• IgG1 monoclonal antibody against soluble Aß (oligomers/protofibrils)

  —> high selectivity over monomers

• targets early Alzheimer´s Disease (phase 2b trial: symptomatic patients)

• to find the best doses more quickly

• without patients or doctors knowing who received which treatment

• Participants were assigned to experimental groups that were more likely to achieve a desired effect -> effective treatment

Soluble amyloid protofibrils = more toxic to nerve cells than solid plaques

• missed its main goal at 12 months

• but after 18 months it showed clear benefits

  • reduced brain amyloid

  • slowed memory decline

• LRP1 = lipoprotein receptor related protein 1

• responsible for Aß transcytosis from brain into the blood

—> regulates the density of LRP1 by binding and targeting them for lysosomal degradation

• PCSK9 high —> LRP low —> impaired clearance from Aß in the brain

side effects more severe than the cognitive outcome

—> 20% of the nerve cells are already dead —> no recovery

—> application should be 5-10 years prior to onset

• approved for hypercholesterolemia

• reducing plasma cholesterole

• Alirocumab and Evolocumab

• only in vitro and mice experiments for AD, no approvement

in vitro: blocking LRP1 with an antibody or removing LRP1 from brain endothelial cells stopped PCSK9 from reducing Aβ transport

in vivo: when LRP1 was removed only from the brain blood vessels, PCSK9 inhibitors no longer lowered the amount of Aβ in the brain. This shows that the effect of PCSK9 works through LRP1.

• mechanism

  • bind to PCSK9

  • stop it from destroying LRP1 and LDL receptors

  • more receptors stay on the cell surface

  • more Aß can transported from brain into the blood

• not found in the brain or spinal fluid

  —> treatment can work from outside the brain and does not need to cross the blood‑brain barrier

• higher LRP1 levels in the liver after PCSK9 treatment may also help clear Aβ from the brain

• it proposes that strong removal of Aβ from the blood (e.g. by the liver) pulls more Aβ out of the brain and stops it from coming back in

• Alirocumab and Evolocumab: male in their 50s —> beneficial effect missing

• we have no clue what the outcome is

  • Better if it is low or high in the blood? —> we don´t know!

• same problem as with lecanemab

—> we have to make them comparable

—> add stressors and take them into account

—> built a regression curve

—> measure the distance to regression line

—> build Stressor reactivity score

= maintenance or quick recovery of mental health during/after periods of adversity (good long-term mental health outcome despite adversity such as traumatic events)

NOT:

• predictor/biomarker (“resilience factor”)

• specific process leading to the outcome (“resilience processes”)

• vulnerability

difference in participants' expectancy of receiving an electric shock (US-expectancy) between

• the first

• and fourth

presentation of the conditioned stimulus (CS+)

Yes, the study shows that poorer extinction learning before trauma leads to more severe PTSD symptoms later. This supports exposure-based therapies, which help train the brain to "unlearn" fear.

• only young male soldiers

• fear was measured only by what participants reported, not by physical responses like sweat

• very early (PTSD usually 6 month)

No —> placebo-controlled interventional study needed

(this is an observational study)

Early intervention with CIPE is beneficial when

• provided within two months after trauma exposure

• and potential risks include mild to moderate adverse events such as

  • increased intrusive memories

  • anxiety

  • depressive symptoms

  • and distress during exposure

  • though no severe adverse events were reported.

remains unclear

(CIPE is evaluated as a scalable digital intervention but makes no comparison about replacement versus complement.)

Resilience: facilitates CIPE therapy

Comorbidities: Individuals with comorbidities were excluded from the study

Type of trauma: no analysis was conducted on whether certain trauma types responded better than others

6 hormones

—> fluctuation of hormone levels rather than the hormones like oestradiol itself

—> depressive disorders in females are 2x higher than in males

mice do not have gender, only sex

= complex, whole-body system that enables one to respond, recover, and adapt from adverse (demanding or threatening) events

= any disruption to an organism’s homeostatic functioning, whether due to

• Perceived psychological stressors:

  • worry, anxiety, fear, uncertainty

• Physical stressors:

  • immune system challenges, physical pain or injury, temperature changes, thirst, exercise

• Hypothalamus

  = Paraventricular nucleus

  • corticotropin releasing hormone (CRH) neurons

• Pituitary

  = corticotrophin cells

  • adrenocorticotropin releasing hormone (ACTH)

• Adrenal glands

  = adrenal cortex cells

  • glucocorticoids

    • —> Cortisol in humans

    • —> Corticosterone in mice

limitation: CORT negative-feedback suppresses CRH neurons and corticotrophs to limit its own production

depression can be associated with

• elevated levels of cortisol

• impaired glucocorticoid feedback

studies showed heightened cortisol secretion under non-stressed conditions

• 43% of persons with MDD = major depressive disorder

• 67% with psychotic depression

yes -> easier to work with male mice

• false assumption: the oestrous cycle (menstrual cycle of rodents) causes huge behavioural fluctuations compared to that of male behaviour

• fluctuations due to hormone cyclicity are crucial to understanding sex differences

Male mice are aggressive, territorial, hierarchical

But female (laboratory) mice are not

—> modification necessary

1. Mask scent of female with male urine

2. VMH neuronal activation to induce male aggression

3. Male attacks pair of mice, both female and male

4. Vicarious social defeat stress model (witness stress)

Female attacks female…

1. Pregnancy and lactation enhances female aggression

   = lactating mother

2. terrotorial female with male partner (defends her territory)

= CNSDS

= Chronic Non-Discriminatory Social Defeat Stress

30 male and 30 female C57BL/6J mice

• Simultaneous exposure of male and female mice to CD-1 aggressor mice = CD-1-Bully (attackts female and male)

• 5 min daily female and male mice with CD-1-Bully

• 24 hours sensory exposure alone without physical interaction (Partition wall)

<-> Control group: co-housed (15 male, 15 female) —> Interactions for equal 5 min intervals without aggressor

—> males were attacked faster and more often

—> no significant effect of estrous cycle on attacking of female mice

• susceptible (SUS): interaction ratio score < 1

  • showed more avoidant and anxious behaviour

• resilient (RES): interaction score > 1

• A key difference was in stress hormone response:

  • SUS mice of both sexes

    —> Stress related behavioural and neuroendocrine changes in SUS

  • RES males had activated HPA axes (elevated corticosterone)

    <-> RES females did not show a significant rise in corticosterone compared to their normal baseline levels.

• molecular analysis

  • increase in HPA axis activation

    • elevated plasma corticosterone levels

    • collecting blood samples via the retro-orbital sinus before and after the 10-day stress protocol (CNSDS) and analyzing the plasma using a corticosterone ELISA kit

• behavioural tests

  • Social interaction test (SIT)

    —> division in susceptible (SUS) and resilient (RES) cohorts

  • Light dark (LD)

    —> stressed mice more in dark

  • Elevated plus maze (EPM)

  • Novelty suppressed feeding (NSF)

  • Sucrose preference test

    —> stressed mice don´t care about sugar anymore

• it’s a simple, surgery-free method

• stresses both male and female mice at once

• easier to compare sexes directly and include more females in stress research

• subordinate vulnerable under social instability

• dominant females more vulnerable to social isolation.

• These disparate stress responses are reflected in rank-specific neuronal activation patterns across multiple brain regions.

• social instability: frequently changing social partners

  • greater vulnerability of Subordinate females

  • more susceptible to social uncertainty

• social isolation: being housed alone = total loneliness

  • greater vulnerability of dominant females

  • more susceptible to the consequences of social isolation

= marker of neuronal activation

• indicates active brain regions after social experience

monoamine hypothesis:

clinical depression = dysregulation of monoamine neurotransmitters in the brain

• specifically serotonin

• norepinephrine

• dopamine

—> must work on neurotransmitter system

—> treatments targets = neurotransmitters

—> 30% have treatment resistant depression

—> new treatments required

• gut-brain axis

• neuroplasticity

• circadian rhythm

• inflammation

• mitochondrium

• metabolism

—> looking at biological systems beyond the brain

• brain as organ of interest (in human studies you can only look at CSF/images/post-mortal tissues

• environmental factors can be controlled

• from bench to bedside

• translation to humans

• KO mice: DBA/2J = reduced inhibitory HPA axis feedback —> innate anxiety

= specialized proteins that support the growth/survival of neurons in brain regions governing mood and memory

• BDNF (higher in Ketamine, Fluoxetine)

• Inhibitors of monoamine reuptake

  • Selective Serotonin Reuptake Inhibitor (SSRI) e.g. Fluoxetine

• monoamine receptor antagonists

  • blocking specific receptor subtypes to prevent neurotransmitters from binding

  • e.g. Mirtazapine blocks specific adrenergic receptors to increase neurotransmitter release (blocks negative feedback)

• monoamine oxidase inhibitors (MAOIs)

  • inhibiting monoamine oxidase

    —> No break down of neurotransmitters e.g. Phenelzine

• melatonin receptor agonists

  • Agomelatine

    = melatonin receptor agonist, serotonin receptor antagonist

• ketamine

  = NMDA receptor antagonist

= Long-term effects of antidepressants like fluoxetine

• neuroplasticity

• neurogenesis

role in Ketamine

• Ketamine = NMDA receptor antagonist

  —> work through glutamate receptors involved in synaptic plasticity

No, but investigate depression-like behaviour and outcomes

= SSRI = selective serotonin reuptake inhibitor

• blocks serotonin transporter

  —> more serotonin in the synaptic cleft

• long-term effects: modulation of neuroplasticity and neurogenesis

• elevates BDNF

= NMDA receptor antagonist

• Glutamate binds on NMDA receptore —> excitatory neurotransmission

• has some affinity for many other receptors

• elevates BDNF

• range of side effects

• metabolite of Ketamine

• no NMDA receptor antagonist!

• similar efficacy

• less side effects

• enhances AMPA receptor activity

= selective serotonin reuptake inhibitor (SSRI)

• increasing serotonin levels in the synaptic cleft

• "resetting" gene activity in the amygdala (emotional center)

  —> specifically normalizes stress-damaged genes

Both treatments work, but different:

• Fluoxetine resets nearly all the genes damaged by stress

• environmental enrichment uses other pathway

—> brain has multiple ways to achieve the same healthy outcome

• GR signaling (initial and sustained)

• long term repair (after initial inhibition)

  • myelin sheath

  • cytoskeleton

• mTOR and BNDF

= hereditary movement disorder by involuntary movements caused by degeneration of the striatum

On-set: Striatum (Nucleus, Putamen) —> medium spiny neurons (MSN)

later: cortical regions

genetically disease

—> treatment before neurodegenerative disease possible

= cause of HD: CAG repeat in gene huntingtin = trinucleotide expansion

• autosomal-dominant

• trinucleotide expression (CAG repeats) in the gene huntingtin

• founder effect

  • European´s much more affected

  • nr. of CAG repeats is crucial

• differences in transmission

  • maternal: rarely changes in CAG n

  • paternal: usually expands (mean expansion 6,2)

    • quality control in sperms not as well as egg quality control

defined by motor symptoms

• comedian tongue (retract their tongue)

• unvoluntary movements, SYMMETRICAL

• hyperactivity —> lack of motor control

• Rigidity

• impaired fine motor skills

other symptoms

• involuntary emotion

• behaviorial changes

• visual disturbances

• dementia

• depression

• psychosis

= very big protein, post-translationally processed

—> seems to play a role in development, (axonal transport, synaptic functions)

≥ 39 (80% with 39 repeats will develop HD)

—> CAG repeats cause the onset and correlate with the age of onset

typical age of onset: 45

• protein misfolding/aggregation

• toxic fragment

only 3 nucleotides —> probability of the onset higher

decreases 15 years before onset

= clinical features in correlation with the age of onset

—> inhibition of Dopa

Disease prediction —> neurodegeneration begins many years before clinical diagnosis = potential window for intervention

imaging biomarkers

• striatal atrophy

• cortical thinning

fluid biomarkers

• mutant huntigtin (mHTT)

• neurofilament light chain (NfL)

• repeats can form hairpin structures

• additional CAG repeats are incorporated

MutSß: recognizes hairpin —> more repeat expansion

MutLα: promotes expansion

FAN1: counteracts repeat expansion —> slows expansion

• delivery across BBB

• long and early preclinical phase

• unknown safety of DNA repair modulation

—> not identifying targets, but deliver a safe, long-term intervention early enough

• predicted with genetic precision

• carriers of the mutation can be identified decades before the first symptoms appear

Certain body cells, particularly in the brain, slowly accumulate longer CAG repeats in the HTT gene

= somatic expansion

—> Huntington’s disease emerges only when these repeats cross a critical toxic threshold, leading to the death of nerve cells

e.g. DNA repair genes involved in mismatch repair

• regulate how quickly the CAG repeat lengthens in vulnerable tissues like the brain

• identifies a "critical window of vulnerability" to detect primal neuronal network changes up to 20 years before the onset

• Targeting this early period = key to therapy

—> offering a chance to stabilize or reverse network dysfunction before irreversible brain damage occurs

= FDA approved drug for Diabetes Type II

Metformin

• disrupts the MID1/PP2A/mTOR complex

• boosting PP2A activity

• reducing mTOR/S6 signaling

—> lowering mutant huntingtin (mHTT9 mRNA translation

(This mechanism was confirmed by loss of effect when PP2A is inhibited or MID1 depleted, and by reduced S6 phosphorylation in treated mouse brains.)

= promising early treatment

= inexpensive, FDA-approved drug, favorable safety profile

he does not think it will end in the clinic

—> bei B = kleine Furchtantworte, aber viel weniger stark

BLOCKING (= Lernen der Furchtantwort ist für B geblockt)

Furchtkonditionierung, die auf einer Vorhersage beruht

—> expectation, anticipation

auf dem dopaminabhängigen Vorhersagefehler

mesolimbisches System —> nucleus accumbens, ventral Striatum

—> phasischer Ausstoß von Dopamin bildet Vorhersagefehler ab

DAT1 (Striatum —> Rückfluss in die Präsynapse)

Bei eingeschränkter Funktion: Dopamin bleibt länger im synapt. Spalt —> höhere Lernrate

Rescorla-Wagner-Modell

V(t+1) = V(t)+ α ⋅ [R-V(t)]

V = Value (könnte auch e für expectation sein)

R = Reinforcement 1 = shock; 0 = no shock

t = repetition

α = learning rate e.g. 0,2

wobei [R-V(t)] = prediction errors PE

lambda/PE = tatsächlicher Vorhersagefehler

V(t+1) = V(t)+ α ⋅ [R-V(t)]

0+1 = 0+ 0,2 ⋅ [1-0]

1 = 0,2 ⋅ 1

Extinction learning = learning of safety

= appetitive-like safety process

• driven by mesostriatal dopamine prediction errors when expected aversive stimuli are omitted

Fear acquisition = learning of fear

= aversive prediction errors in a partially separate system

• no influence from striatal dopamine

• can´t explain why fear comes back after extinction

  —> suggests that fear memories are only suppressed by new learning, not completely erased

• can´t explain how the brain separates fear conditioning from extinction, especially how the dopamine system (normally linked to reward) signals safety

= largely correlational

• observational study

• no experimental control —> no definitive causal relationship between dopamine levels and the observed differences in extinction learning

• unique binding site

  • avoids competition with natural ligands

  • lowering systemic side effects compared to the full-length receptor

• When delivered via gene therapy, it also restricts drug delivery specifically to the CNS

depends mainly

• on Rab27a-mediated exocytosis

• the receptor's avoidance of lysosomal degradation.

Transport rates also vary with temperature and competition for the receptor's binding site.

• whether overexpressing this artificial receptor in living organisms causes

  • immune reactions

  • safety issues

• how it affects other natural receptors on the blood-brain barrier

• how drug-filled liposomes work under real-life conditions

• develop viral vectors that only target human brain endothelial cells

  
  

proved that changes in Aβ removal were due to loss of LRP1 transport, not just passive leakage

—> using reference markers like [14C]-inulin confirmed that the barrier was not damaged

—> accurate measurement of active receptor-mediated clearance

• LRP1 handles about half of the fast clearance across the blood-brain barrier

  = main route for removing toxic brain peptides

• very fast endocytosis rate

  —> outperforms other receptors

5xFAD mice without endothelial LRP1 have

• severe learning and memory problems

• higher levels of soluble Aβ, even though their plaque buildup stayed the same

—> These results support clinical findings that soluble Aβ levels are linked to how severe nerve damage is, while plaques mainly just show that the disease is present

to test if

• inhibiting chronic microglial activation (CMA)

• could slow progressive neurodegeneration

• at least six months after traumatic brain injury

Minocycline was thought to be neuroprotective

• increased plasma NfL (a marker of active axonal injury)

• levels returned to baseline after stopping the drug

—> Microglia may have supportive functions

= small sample size

• designed to detect PET changes, not clinical outcomes

—> impact of elevated levels of the neurodegeneration marker NfL on patients' daily lives remains unclear

• major risk = off‑target effects on other tissue‑resident macrophages

  • could weaken peripheral immune responses

• translation to humans remains unclear

  • as microglial depletion worsened neurotoxicity and inflammation in stroke and Parkinson’s disease

No

• transcriptomic analysis can´t isolate the role of microglia alone

• Benefits might come from altered responses in other cells (e.g., neurons or astrocytes) within the changed lesion environment

Transient depletion acts as a "reset"

• removes chronic toxic microglia

• allows new, more homeostatic and less inflammatory microglia to repopulate.

Constant suppression

• would block essential microglial functions like tissue repair.

• they restore intracellular glucose very slowly after energy‑demanding activity

• low levels of glucose transporters and glycolysis‑related genes compared to mature neurons

Astrocytes

• surround newborn neurons in a nest‑like pattern

• highly express glycolytic genes like Aldoc

functional imaging shows, that astrocytes

• quickly rebalance glucose

• increase lactate production

• export during hippocampal activity

glucose —> lactate —> lactate release

—> MCT1 transporters —> neurons —-> TCA cycle

through TCA cycle they fuel the high metabolic demands for growth and survival during circuit integration

• strongest in the molecular layer (ML) of the dentate gyrus with increased

  • cell number

  • nucleus size

  • activation markers

—> new neurons form afferent synapses there, making them sensitive to the local microglial environment during integration.

Over‑accumulation of ECM components

• creates a "non‑permissive milieu" by forming a dense proteoglycan network

  —> hinders plasticity

• causes neurite tips to bind too tightly to the matrix

  —> physically stops neurons from moving and dendrites from growing longer

• enlarged postsynaptic density (PSD)

  —> presynaptic active zone lacks synaptic vesicles —> functionally impaired PSD

—> presynaptic side cannot release neurotransmitters effectively, making the connection functionally "silent"

• noninvasive

• avoiding surgery of implanted leads

• lower costs

• greater flexibility

Sadness subscale of the PANAS-X

—> to measure immediate mood changes after stimulation

6‑item Hamilton Depression Rating Scale (HDRS‑6)

—> For longer‑term depressive symptom severity

• imperfect ultrasound correction/slight variations in targeting location

  —> may cause differences in response

• individual anatomical differences

  —> more personalized targeting for consistent deactivation may be needed

~79% remission rate

• nearly double that of electroconvulsive therapy (the current gold standard)

• far exceeds the ~17 % rate seen with standard rTMS in treatment‑resistant patients

After SNT, patients would ideally switch to less intensive maintenance therapies (e.g., medication or psychotherapy) to sustain remission

= five‑day SNT protocol

• reduces the standard six‑week treatment

• treat severely depressed patients in emergency

—> targeting the DLPFC‑sgACC circuit can induce rapid remission in most highly treatment‑resistant patients

Challenges

• need for larger multi‑site trials to confirm generalizability

• further research on long‑term durability compared to other active protocols