Lecture 11: Alzheimer’s
A chronic degenerative brain disorder related to aging
Minor forgetfulness; major memory disruptions; generalized dementia; widespread
psychological dysfunction; death
60-70% of dementia
Epidemiology
● Post mortem
○ Diagnosis is based on characteristic clinical features
○ Confirmed only by distinctive cellular pathology in post mortem brain tissue
● Most AD patients die of unrelated complication
Symptoms
Early
● Short term memory loss
● Subtle problems with executive function
● Apathy
Later stages
● Language difficulty, disorientation
● Mood swings
Advanced
● Loss of motivation and bodily functions
● Dependent on caregivers
Neuropathology
● Loss of neurons and synapses in specific and predictable brain regions
● Both extracellular amyloid plaques and intracellular neurofibrillary tangles are clearly
visible by microscopy in brains of AD patients (these remain as the stereotypical
hallmarks of the disease)
● Mass shrinking of cortical thickness can be observed in late stages of the disease
● Degeneration of dendritic trees/branches and general atrophy of neurons
● Physical changes: associated with worsening of symptoms
Development
● Genetic predisposition (approx 70% of risk)
● Exposure to environmental elements (aluminum)
● Immune reactions
● Slow viruses
● Prions: abnormal infectious forms of proteins
Two principle neuronal changes that occur in AD patients
1. Loss of cholinergic cells in the basal forebrain
2. Development of neuritic plaques and tangles in the cerebral cortex
Acetylcholine NT
● Ach was amongst the first NT ever discovered
, ● Widely distributed throughout the brain and plays a crucial role in both sympathetic
and parasympathetic branches of the ANS as well as the CNS
● Ach is responsible for muscle contractions as it releases neuromuscular junctions
○ Many drugs, cosmetics and toxins act on the cholinergic system
○ Botulinum Toxin inhibits Ach release
Cholinergic cell bodies are located in two regions:
1. Basal forebrain: projects to the
hippocampus and cortex
2. Midbrain: project to the basal
ganglia, thalamus, diencephalon,
cranial nerve nuclei and reticular
formation
● Ach neurons in the basal ganglia
are involved in cognitive
function , particularly in learning
and memory
○ Drugs that increase
activity of ACh enhance
memory
○ Disruptions to CNS ACh
NT impair memory
● Cells in the basal forebrain are among the first to die in AD
○ Specifically in the entorhinal cortex
○ Neurodegeneration spread outwards and extends into the cerebral cortex as
disease progresses
Ach neurons in the BG are involved in cognitive function, particularly learning and memory
● Drugs that increase activity of Ach enhance memory
● Disruption to the CNs ACh NOT impair
memory
Neuritic plaques
● Main pathological features of AD plaques
and neurofibrillary tangles
● These plaques and tangles interfere with
normal processing of AP’s and cellular
function
● Neuritic plaques are composed of central
core of homogeneous protein (b-amyloid)
○ B amyloid is product of amyloid
precursor protein, which is
involved in activation of kinases,
protection against oxidative
stress, reg of cholesterol
transport
, ● Plaques are not distributed evenly throughout the cortex but are concentrated in the
temporal lobe areas involved in memory
● Plaques are also associated with neurofibrillary tangles which are paired helical
filaments found in cerebral cortex and hippocampus
Neurofibrillary tangles
● Cytoskeleton : evolutionary solution to maintaining a neuron’s 3D structure as well as
guide transport of proteins and molecules across vast distances
○ Cytoskeletal functions as both flexible scaffold and transportation system
Three main components to the cytoskeleton
1. Neurofilaments: control and transport of membrane proteins
2. Microtubules: control the transfer/movement of substances and organelles
throughout the cytoplasm
3. Microfilaments: provides structural support to axons and dendrites
Tau proteins
● Stabilization and flexibility of microtubules and microfilaments
● Hyperphosphorylated tau proteins begin to accumulate, eventually forming
aggregates (neurofibrillary tangles) inside cell bodies
● Consequence: microtubules disintegrate and ultimately destroy the structure of the
cytoskeleton
○ Major collapse to neurons transport system
○ Malfunctions in biochemical pathways and communication between neurons
○ Cell death
But how?
● Genetic component to AD, but heritability ranges
● Twin studies suggest between 49-79 percent heritability
○ Several genes are implicated in AD
● One of the genes most commonly indicated codes for APP which is located on
chromosome 21
○ Involved in many neurons, concentrated at the synapse
○ Implicated in synapse formation and synaptic plasticity
○ Proteolysis product is the B-amyloid protein
● APP gene is located on chromosome 21. Trimosy 21 patients universally exhibit early
AD symptoms (age 40)
● Environment: acute exposure and poisoning from heavy metals and pesticides is a
known risk for AD; air pollution (organic and non-organic compounds, metal gases
that can be toxic)
○ growing evidence that suggests that polluted air is linked to
neurodegeneration and AD
○ Many people cannot control their exposure to polluted air
Management and treatment
● No cure for AD
● Drugs that increase ACh NT have been shown to improve cognitive symptoms of AD
A chronic degenerative brain disorder related to aging
Minor forgetfulness; major memory disruptions; generalized dementia; widespread
psychological dysfunction; death
60-70% of dementia
Epidemiology
● Post mortem
○ Diagnosis is based on characteristic clinical features
○ Confirmed only by distinctive cellular pathology in post mortem brain tissue
● Most AD patients die of unrelated complication
Symptoms
Early
● Short term memory loss
● Subtle problems with executive function
● Apathy
Later stages
● Language difficulty, disorientation
● Mood swings
Advanced
● Loss of motivation and bodily functions
● Dependent on caregivers
Neuropathology
● Loss of neurons and synapses in specific and predictable brain regions
● Both extracellular amyloid plaques and intracellular neurofibrillary tangles are clearly
visible by microscopy in brains of AD patients (these remain as the stereotypical
hallmarks of the disease)
● Mass shrinking of cortical thickness can be observed in late stages of the disease
● Degeneration of dendritic trees/branches and general atrophy of neurons
● Physical changes: associated with worsening of symptoms
Development
● Genetic predisposition (approx 70% of risk)
● Exposure to environmental elements (aluminum)
● Immune reactions
● Slow viruses
● Prions: abnormal infectious forms of proteins
Two principle neuronal changes that occur in AD patients
1. Loss of cholinergic cells in the basal forebrain
2. Development of neuritic plaques and tangles in the cerebral cortex
Acetylcholine NT
● Ach was amongst the first NT ever discovered
, ● Widely distributed throughout the brain and plays a crucial role in both sympathetic
and parasympathetic branches of the ANS as well as the CNS
● Ach is responsible for muscle contractions as it releases neuromuscular junctions
○ Many drugs, cosmetics and toxins act on the cholinergic system
○ Botulinum Toxin inhibits Ach release
Cholinergic cell bodies are located in two regions:
1. Basal forebrain: projects to the
hippocampus and cortex
2. Midbrain: project to the basal
ganglia, thalamus, diencephalon,
cranial nerve nuclei and reticular
formation
● Ach neurons in the basal ganglia
are involved in cognitive
function , particularly in learning
and memory
○ Drugs that increase
activity of ACh enhance
memory
○ Disruptions to CNS ACh
NT impair memory
● Cells in the basal forebrain are among the first to die in AD
○ Specifically in the entorhinal cortex
○ Neurodegeneration spread outwards and extends into the cerebral cortex as
disease progresses
Ach neurons in the BG are involved in cognitive function, particularly learning and memory
● Drugs that increase activity of Ach enhance memory
● Disruption to the CNs ACh NOT impair
memory
Neuritic plaques
● Main pathological features of AD plaques
and neurofibrillary tangles
● These plaques and tangles interfere with
normal processing of AP’s and cellular
function
● Neuritic plaques are composed of central
core of homogeneous protein (b-amyloid)
○ B amyloid is product of amyloid
precursor protein, which is
involved in activation of kinases,
protection against oxidative
stress, reg of cholesterol
transport
, ● Plaques are not distributed evenly throughout the cortex but are concentrated in the
temporal lobe areas involved in memory
● Plaques are also associated with neurofibrillary tangles which are paired helical
filaments found in cerebral cortex and hippocampus
Neurofibrillary tangles
● Cytoskeleton : evolutionary solution to maintaining a neuron’s 3D structure as well as
guide transport of proteins and molecules across vast distances
○ Cytoskeletal functions as both flexible scaffold and transportation system
Three main components to the cytoskeleton
1. Neurofilaments: control and transport of membrane proteins
2. Microtubules: control the transfer/movement of substances and organelles
throughout the cytoplasm
3. Microfilaments: provides structural support to axons and dendrites
Tau proteins
● Stabilization and flexibility of microtubules and microfilaments
● Hyperphosphorylated tau proteins begin to accumulate, eventually forming
aggregates (neurofibrillary tangles) inside cell bodies
● Consequence: microtubules disintegrate and ultimately destroy the structure of the
cytoskeleton
○ Major collapse to neurons transport system
○ Malfunctions in biochemical pathways and communication between neurons
○ Cell death
But how?
● Genetic component to AD, but heritability ranges
● Twin studies suggest between 49-79 percent heritability
○ Several genes are implicated in AD
● One of the genes most commonly indicated codes for APP which is located on
chromosome 21
○ Involved in many neurons, concentrated at the synapse
○ Implicated in synapse formation and synaptic plasticity
○ Proteolysis product is the B-amyloid protein
● APP gene is located on chromosome 21. Trimosy 21 patients universally exhibit early
AD symptoms (age 40)
● Environment: acute exposure and poisoning from heavy metals and pesticides is a
known risk for AD; air pollution (organic and non-organic compounds, metal gases
that can be toxic)
○ growing evidence that suggests that polluted air is linked to
neurodegeneration and AD
○ Many people cannot control their exposure to polluted air
Management and treatment
● No cure for AD
● Drugs that increase ACh NT have been shown to improve cognitive symptoms of AD
