Amyloid diseases

Alzheimer's disease

Parkinson's disease

Amyotrophic lateral sclerosis (ALS)

Progressive

Lethal

The most common form of dementia (60-70% of all cases)

Prevalence increases with age

50 million people worldwide

8-10 years to live after diagnosis

10 million new cases per year

AD is believed to begin at least 20 years prior to diagnosis

10% over age of 65 has AD

No cure, only symotomatic treatment

Clinical manifestations

Mild Cognitive Impairment

Mild Alzheimer's

Moderate Alzheimer's

Severe Alzheimer's

Disease begins in Medial Temporal Lobe

Disease spreads to Lateral Temporal and Parietal lobes

Disease spreads to Frontal lobe

Disease spreads to Occipital lobe

AD Molecular pathology

  1. Amyloid-β
  1. Tau

Cleavage of (Amyloid prcursor protein) APP generates 37-42 residues long
A\(\beta\) peptides

Pathological mutations associated with early onset hereditary AD

90% A\(\beta\)(1-40)

~5% A\(\beta\)(1-42)

More aggregation prone, disease-associated variant

Amyloid cascade hypothesis

"Our hypothesis is that the deposition of amyloid \(\beta\) protein, the main component of the plaques, is the causative agent of Amzheimer's pathology and that the neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition."

Inhereted AD - Amyloid-\(\beta\) mutations

Trisomy21 (Down's syndrome)

3 copies of the APP gene

Mutations in enzymes processing APP into A\(\beta\)

More aggregation prone A\(\beta\)(1-42)

Aggregation-promotion A\(\beta\) variants

Arctic: E22G

Microtubule-associated protein

Stabilizes microtubule

Important for the morphology and physiology of neurons

Six isoforms, varying in length and number of repeats

Acidic N-terminal domain
Basic C-terminal domain

Treatments

Cholineesterase inhibitors

NMDA antagonists/glutamate regulators

Support function of synapse, but do not prevent degeneration

In development

Antibody-based therapies directed to A\(\beta\)

Phase III clinical trials (aducanumab, Biogen)

BAN2401 (Bioarctic, Uppsala)

Progressive

Loss of dopaminergic neurons

Not fatal

2nd most common neurodegenerative disorder after AD

10 million people worldwide

Incidence increases with age

~1% over age of 60 has PD

Symptoms can be slowed down, but not halted

Hereditary, sporadic, environmental

Clinical symptoms

Tremor (typically starts in one hand)

Bradykinesia (slowed movement)

Rigid mucles

Impaired posture and balance

Loss of automatic movement

Speech changes

Molecular pathology

\(\alpha\)-synuclein

14kDa preynaptic protein

Intrinsically disordered

Inhereted PD: \(\alpha\)-syn mutations

Duplication of the snca gene (encoding \(\alpha\)-syn)

Point mutations

A30P

E46K

H50Q

G51D

A53T/E/V

Treatments

Levodopa (metabolic precursor of dopamine)

Effective against muscle rigidity and slowed movement

Reduced effect over time

Dopamine receptor agonists (many variants)

Carbidopa (L-dopa structural analog; reduces side effects)

Side effects is a problem with most PD treatments

Rapidly progressive

Paralysis disorder

Affects motor neurons in spinal cord and brain

Lethal (respiratory failure)

Life expectancy after diagnosis: 2-5 years

Mean age of onset: 55

Estimated 450.000 people worldwide live with ALS

Incidence: ~2/100.000 people (rare)

No cure

Only symptomatic treatment

Clinical Manifestations

Early Stages of ALS

Middle stages of ALS

Late stagesof ALS

Muscle weakness

Muscle twitching

Muscle cramping

Poor balance

Fatigue

Slurred speech

More severe muscle weakness

Paralysis in some muscles

Difficulty in swallowing

Difficulty in eating/chewing

Breathing issues

Bouts of uncontrollable laughter or crying (aseudobulbar affect)

Paralysis in most muscles

Extreamly limited mobility

Inability to speak

Inability to breath without assistance

Inability to eat without assistance

Inability to drink without assistance

Molecular pathology

TDP-43

FUS

SOD-1

Shared with FTLD (frontotemporal lobar dementia; although affecting different parts of the CNS/brain)

TAR DNA-binding protein 43 kDa

Transcriptional repressor

Splicing regulator

Nuclear localisation

Involved in stress regulation (cytoplasmic role)

Forms inclusions in 97% of patients with ALS

Inclusions also found in significant subsets of patients with AD, Huntington and other neurodegenerative disorders

Inclusion formation

Liquid-liquid phase separation (LLPS) AND amyloid formation

C-terminal truncations common (releases c-terminal amyloidogenic segments; 25kDa, 35kDa

Treatments

Symptomatic treatment

Life-prolonging (but typically only by a few months)

Medicines

Riluzole

Thought to inhibit synaptic glutamate release

Edarvone (2017)

Free radical scavenger, oxidative stress reduction

Mechanical ventilation

Avoid death due to respiratory failure