ACh 3

Question 1

Type of transmission in basal forebrain cholinergic pathways>?

Answer 1

both wired and volume

Question 2

cholinergic pathways in the brain

Answer 2

Diagram

Question 3

Nucleus Basalis of Meynert

Answer 3

Considered to be the site of confluence of the
limbic system and the ascending arousal system • Non-cholinergic cells include GABAergic,
peptidergic and NADPH diaphorase positive types
(nNOS?) • Receives input selectively from limbic cortices
and amygdala (NOT all cortices) • Receives brain stem input – dopaminergic,
tryptaminergic and noradrenergic • Receives cholinergic input – from Ch1-3, and/or
pontine groups

Question 4

ACh and cognition

Answer 4

o Working memory
o Attention
o Episodic memory
o Spatial memory

Question 5

Discovery of Alzheimer’s disease

Answer 5

First described by Alois Alzheimer in 1902.
• First patient, Auguste Deter, said: “I seem to
have lost myself”. She died 5 years after her
diagnostic.
• Alzheimer called it “Disease of
forgetfulness”.
• Originally considered to be pre-senile
dementia, but now we know is the most
common form of dementia in the elderly.

Question 6

Epidemiology of Alzheimer’s disease

Answer 6

The most common neurodegenerative disease, accounting
for >80% of total dementia cases in the elderly.
• There are currently 47 million sufferers worldwide and it is
predicted this will grow to 130 million by 2050 because of
increase in life expectancy.
• In 2015, the annual societal and economic cost of
dementia was US$818 billion worldwide. This amount is
expected to increase to 1 trillion by 2018.
• In England and Wales 163,000 new cases every year (one
every 3.2 minutes).

Question 7

Clinical manifestations of Alzheimer’s disease

Answer 7

Symptom pattern begins with
progressive decline in ability to
remember new information.
• Disruption of neuronal function
usually begins in brain regions
involved in forming new memories.
• Progression from episodic memory
problems to global decline of
cognitive function.

Question 8

Anatomopathology of Alzheimer’s disease

Answer 8

Progressive loss of synaptic
neurons
• Atrophy of hippocampus,
frontal and temporoparietal
cortex
• Accumulation of amyloid beta
(Aβ) plaques around neurons • Hyperphosphorylated
microtubules associated with
tau protein in the form of
intracellular neurofibrillary
tangles (NFT)

Question 9

Pathogenesis of Alzheimer’s disease

Answer 9

Unknown; multifactorial • Cholinergic transmission • Excessive protein misfolding and Aβ aggregation • Oxidative stress and free radical formation • Metal dyshomeostasis • Excitotoxic and neuroinflammatory processes • Tau pathology

Question 10

Cholinergic hypothesis of Alzheimer’s

Answer 10

Degeneration of neurons
from the cholinergic nuclei in
the basal forebrain region
(specially the nucleus basalis
of Meynert) and their
terminals in the
hippocampus.
• Hippocampal atrophy and ventricle enlargement.
• No effect on Brainstem Cholinergic Pathways(?)

Question 11

Acetylcholinesterase

Answer 11

Peripheral anionic site (PAS)
important in AD.
• Interaction of Aβ and PAS
contributes to formation of
amyloid plaques

Question 12

Butyrylcholinesterase

Answer 12

Expressed in the hippocampus and temporal neocortex but at lower levels than AChE. Mainly present in endothelia, glia and
neuronal cells with low affinity for ACh.
• In AD brain, BuChE associates with Aβ protein and may delay
onset and rate of neurotoxic Aβ fibril formation.
• In AD, there is a progressive increase of BuChE:AChE ratio
associated with amyloid plaques and NFTs, and with gradual loss
of cognition function.

Question 13

amyloid hypothesis

Answer 13

Diagram

Question 14

neuroinflammation

Answer 14

diagram

Question 15

Tau pathology

Answer 15

Diagram

Question 16

Tacrine

Answer 16

Competitive AChE inhibitor and mAchRs modulator competitive (withdrawn)

Question 17

Rivastigmine

Answer 17

Non-selective pseudoreversible ChE inhibitor

Question 18

Galantamine

Answer 18

1) Reversible/competitive selective AChE inhibitor and nicotinic receptor modulator
2) NMDA receptor temptation

Question 19

Donepezil

Answer 19

Reversible non-competitive ChE inhibitor

Question 20

Memantine

Answer 20

1) NMDA receptor antagonist
2) Neuroprotective
and nAChRs (Aβ toxicity, tau phosphorylation,
neuroinflammation,
oxidative stress)

Question 21

Therapies against Aβ

Answer 21

• Anti-Aβ immunotherapy:
antibodies against APP,
monomeric Aβ, soluble Aβ
oligomers, insoluble Aβ fibrils,
Aβ carrier proteins and
transport channels.
• γ- and β-secretase inhibitors

Question 22

Tau-targeted therapies

Answer 22

• Tau pathology may be the cause of Aβ pathology.
• Strategies:
1. Inhibition tau fibril
formation (chemical) 3

2. Promotion abnormal tau
   clearance (antibodies, vaccination) 3. Inhibition tau aggregation