Alzheimers

Question 1

Neurodegenerative disorders

Answer 1

Any disease that is marked by the progressive loss of neurons
-Huntingtons disease
-Amyotrophic lateral sclerosis
-Alzheimers disease
-Parkinsons disease
-Prion diseases

Many NDs are associated with abnormal intra or extracellular protein aggregations in the brain

Question 2

Alzheimers disease

Answer 2

Prevalence and symptoms
Affects 5% of people over 70 and 20% of people over 80
Causes loss of memory and decreased attention and motivation
Stress can accelerate progression
Most AD patients also have PD and suffer from depression
Life expectancy after diagnosis is 8 years

Question 3

Neuropathology

Answer 3

Atrophy of subcortical brain regions
Enlargement of cerebral ventricles and brain sulci
30-40% reduction in brain weight

Question 4

Neuritic plaques

Answer 4

Extracellular lesions containing an insoluble form of the peptide beta-amyloid

Question 5

Neurofibrillary tangles

Answer 5

Cytoplasmic bundles of hyper-phosphorylated tau proteins

Question 6

What neurons die in AD

Answer 6

Cholinergic neurons in septum and nucleus basalis of Meyndert = impairment of memory consolidation
Glutamatergic pyramidal cells in the cortex = accounts for most of the cognitive deficits
Noradrenergic and serotonergic neurons

Question 7

AD etiology

Answer 7

Most cases are idiopathic, with possible genetic predisposition.
– The apolipoprotein E (ApoE) e4 allele and loss-of-function
mutations in triggering receptor on myeloid cells 2 (Trem2)
increase risk for developing AD
* Familial AD cases may start early (early-onset AD)
and are caused by mutations in one of three genes– Amyloid precursor protein (APP)– Presenilin 1– Presenilin 2
* Rare protective mutations in APP also occur

Question 8

Familial AD: APP and presenilins

Answer 8

APP is the precursor protein for beta-amyloid
Presenilins are part of the y-secretase complex

Question 9

Protein aggregation

Answer 9

Intermediate protein aggregates are toxic
-inhibition of their formation may promote their clearance and may improve AD symptoms

Formation of final protein aggregates (plaques and tangles) may protect from toxicity
-Inhibition of their formation may cause accumulation of intermediate aggregates and enhance AD symptoms

Question 10

A-beta

Answer 10

Causes mitochondrial dysfunction and inflammation

Question 11

Pharmacological treatment

Answer 11

Acetylcholinesterase inhibitors - improves cholinergic functions. Not very successful.
Anti-inflammatory drugs - targets inflammatory components of AD
Vaccination against AB = not successful. Causes brain inflammation
-Chelating agents = binds Cu and Zn
Antioxidants - bind free oxygen radicals
-Neurotrophins - Proteins that promote neuronal survival and growth.
Inhibitors of beta and gamma secretase

Question 12

Aducanumab/Lecanemab

Answer 12

Anti-amyloid antibodies are given by infusion
Antibodies clear amyloid from the body and brain
Antibodies can promote removal of amyloid before it forms plaques
-Antibodies can bind to plaques that have formed
-Antibodies can trigger immune cells to clear amyloid

Question 13

APP mice

Answer 13

Have no amyloid plaques
Do have hippocampal memory impairments
Molecular mechanisms underlying hippocampal synaptic dysfunction in APP
Increased levels of ECM proteins
ChABC treatment rescues memory deficits in APP
ChABC treatment rescues LTP deficits in APP