neurobiology of disease discussion

Alzheimer’s Disease Dr. Katie Dabrowski, PT, DPT

Alzheimer’s Disease (AD)

• Most common form of dementia • Progressive neurodegenerative disorder • Early symptoms: Difficulty remembering names and recent events,

apathy, depression

• Later symptoms: Worsening memory, impaired judgement, disorientation, confusion, behavioral changes, and difficulty speaking, swallowing, and walking

Neuropathology of AD

Neuropathology of AD: Beta-Amyloid Plaques

Beta-Amyloid Plaques (Aβ)

• Aβ = a protein fragment snipped from an amyloid precursor protein (APP); amyloid plaques are hard, insoluble accumulations of beta proteins that clump together between neurons in AD

• Amyloid Cascade Hypothesis: Proposes that AD is caused by an imbalance between Aβ production and clearance, resulting in increased amounts of Aβ

Beta-Amyloid Plaques (Aβ)

• Normally… • APP is produced in large quantities in neurons, and metabolized very quickly and

ultimately broken down and released as Aβ into the extracellular space • Aβ is then cleared from the CNS via phagocytosis, enzymes, arterial pathways, capillaries

in the brain, etc.

• In AD, it is thought that Aβ becomes deposited in these clearance pathways (arteries, capillaries, etc), resulting in increased levels of Aβ in the brain, which ultimately leads to a cascade of pathological events that lead to: • Neuronal dysfunction • Cell death • Dementia

Progression of Aβ

• Early-onset AD is associated with over-production and elevated levels of Aβ

• Lat—onset AD is associated with decreased Aβ clearance

• Aβ deposits in the brain starting in the neocortex, spreading through the hippocampus, and eventually through the rest of the cortex.

When Aβ becomes problematic

• Cell death occurs due to intracellular accumulation of Aβ • Above normal physiological levels of Aβ can impair synaptic

activity • Normal amounts of Aβ released into the extracellular space is part of a

feedback loop controlling neuronal excitability • Small increases of Aβ facilitate presynaptic function • Intermediate levels of Aβ enhance presynaptic activity • Abnormally low and abnormally high levels of Aβ depress postsynaptic

transmission and lead to a loss of dendritic spines

When Aβ becomes problematic • Elevated glial cell inflammatory response to Aβ

• We know that immune and inflammatory responses are associated with AD – whether these processes are a cause, contributor, or secondary phenomenon

• Microglia play a crucial role in immune/inflammatory response in neurological disorders – they secrete inflammatory factors (reactive oxygen species, T cells, chemokines, growth factors, etc.), which are often elevated in pathological brain regions of AD patients, where Aβ deposits are found

• Astrocytes also play a neurosupportive role in the brain, and reactive astrocytes are found around Aβ deposits, similarly to a glial scar found around an injury or infection (like in SCI)

• Oligodendrocytes produce the myelin sheath around axons to speed up neural transmission – studies show that in areas of Aβ deposits, there is resultant decreased myelination

Neuropathology of AD: Neurofibrillary Tangles

Neurofibrillary Tangles (Tau)

• There are normal, physiologic levels of both phosphorylated and nonphosphorylated forms of tau

• In brains of AD patients, there are findings of hyperphosphorylated tau (4-8x the amount when compared to non-AD brains)

• With hyperphosphorylation of tau, tau becomes insoluble and assembles into coils, ultimately becoming neurofibrillary tangles

When hyperphosphorylated tau becomes problematic • Axonal transport disruption: • Normal tau has cellular functions like stabilizing microtubules, promoting

neurite growth, and facilitating axonal transport

• Hyperphosphorylated tau decreases stability of microtubules and impairs axonal transport

• Decreased cognitive function: • Tau concentrations are high in synaptic terminals of AD patients

Neuropathology of AD: Cell Loss and Structural Dystrophy

Progressive Synaptic Loss and Cognitive Decline

• Synaptic loss in the hippocampus and neocortex is a major structural correlate of cognitive dysfunction • Individuals with AD have up to 55% fewer synapses in CA1 region of

hippocampus than those with no cognitive impairment; 45% fewer than individuals with mild cognitive impairment

Progressive Decrease of Choline Acetyltransferase and Acetylcholinesterase and Cognitive Decline • Choline acetyltransferase (CAT) and acetylcholinesterase (AChE)

activity progressively decreases in patients with AD

• Patients with moderate to severe AD have 25-33% decreases in cortical CAT and AChE activity

• This decreased activity is correlated with deficits in attention and learning and memory

Progression of Structural Atrophy of the Brain in AD • Anatomical signs of AD: • Progressive brain atrophy (particularly in the hippocampus) • Yearly atrophy rate of hippocampus is 4.7% in AD, while healthy age-

matched controls have only 1.4%

• Cortical thinning found in temporal and parietal lobes

Oxidative Stress Hypothesis

Oxidative Stress Hypothesis

• Reactive oxidative species (ROS or free radicals) may mediate oxidative cell injury and cell death • These free radicals come from byproducts of the electron transport chain

(ETC) in the mitochondria

• In AD, there is inhibition of the ETC, resulting in accumulation of electrons and free radical production

Vascular Hypothesis

Vascular Hypothesis

• Proposes that AD develops when two biological events converge: • Advancing age + vascular risk factors for AD

• Vascular risk factors for AD: • Cerebral microvascular pathology • Cerebral hypofusion

• These plus advancing age can trigger the cognitive and degenerative changes in AD

Neurotransmitters and AD

Neurotransmitters in AD • Acetylcholine

• Impaired cortical acetylcholine transmission contributes to Aβ pathology and increases phosphorylation of tau

• Glutamate • Malfunctions in the glutamate-glutamine cycle can result in a neuronal death

cascade and glutamate excitotoxity

• Serotonin • Altered levels of serotonin in CSF (cerebrospinal fluid) and decreases in

serotonin-synthesizing neurons and receptors are found in individuals with AD

• Norepinephrine • Loss of locus coeruleus (LC) neurons in AD (LC neurons produce norepinephrine)