3.22
Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neu…
Alzheimer disease causes progressive structural brain changes, marked by extracellular neuritic plaques and intracellular neurofibrillary tangles.
Neuritic plaques result from abnormal processing of the amyloid precursor protein, leading to the accumulation of beta-amyloid, a toxic peptide that aggregates outside neurons.
These deposits form dense-core plaques in the cerebral cortex and around blood vessels, encircled by dystrophic neurites, astrocytes, and microglia, which disrupt synaptic communication and cause neuronal damage.
Within neurons, tau, a protein that stabilizes microtubules, becomes hyperphosphorylated, detaches from them, and forms twisted strands called neurofibrillary tangles. These tangles disrupt intracellular transport and promote neuronal death.
As the disease progresses, neurons and synapses degenerate in the hippocampus, the entorhinal cortex, and the frontal and temporal lobes, leading to brain atrophy.
The degeneration of cholinergic neurons in the basal forebrain reduces acetylcholine levels, contributing to cognitive and behavioral symptoms.
View the full transcript and gain access to JoVE Core videos
Q1: What are neuritic plaques and how do they form in Alzheimer disease?
Neuritic plaques are extracellular deposits that form in the cerebral cortex and around blood vessels. They result from abnormal processing of amyloid precursor protein, leading to accumulation of beta-amyloid, a toxic peptide that aggregates outside neurons. Each plaque has a dense core surrounded by damaged neuronal extensions, astrocytes, and microglia, disrupting synaptic communication and causing neuronal damage.
Q2: How do neurofibrillary tangles contribute to neuronal death in Alzheimer disease?
Neurofibrillary tangles form when tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and detaches from them. These twisted strands accumulate inside neurons, disrupting intracellular transport and promoting neuronal death. As tangles accumulate throughout the brain, they contribute to progressive neuronal degeneration and cognitive decline.
Q3: Which brain regions are most affected by neuronal degeneration in Alzheimer disease?
The hippocampus, entorhinal cortex, and frontal and temporal lobes experience the most significant neuronal and synaptic degeneration in Alzheimer disease. These regions are responsible for memory and thinking, and their progressive loss leads to brain atrophy, including widened sulci, thinned gyri, and enlarged ventricles. This structural damage correlates with the cognitive symptoms observed in patients.
Q4: What role does acetylcholine deficiency play in Alzheimer disease symptoms?
Degeneration of cholinergic neurons in the basal forebrain reduces acetylcholine levels, a key neurotransmitter for learning and memory. This neurotransmitter depletion, combined with synaptic loss and neural atrophy, contributes significantly to the cognitive and behavioral symptoms characteristic of Alzheimer disease. The loss of cholinergic function directly impairs memory formation and retention.
Q5: How does beta-amyloid accumulation damage neurons in Alzheimer disease?
Beta-amyloid is a toxic peptide fragment that results from abnormal processing of amyloid precursor protein. It aggregates extracellularly to form dense-core plaques surrounded by dystrophic neurites, astrocytes, and microglia. These plaques disrupt synaptic communication between neurons and eventually cause their death, leading to progressive cognitive decline.
Q6: What structural changes occur in the brain as Alzheimer disease progresses?
As Alzheimer disease progresses, neurons and synapses degenerate, causing overall brain atrophy. The brain exhibits widened sulci, thinned gyri, and enlarged ventricles. These structural changes result from the combined effects of neuritic plaques, neurofibrillary tangles, synaptic loss, and cholinergic neuron degeneration, ultimately leading to increased intracranial pressure and further neurological complications.
Q7: How are amyloid precursor protein and tau protein involved in Alzheimer pathology?
Amyloid precursor protein undergoes abnormal processing, generating beta-amyloid that accumulates extracellularly in neuritic plaques. Tau protein normally stabilizes microtubules but becomes hyperphosphorylated in Alzheimer disease, detaching from microtubules and forming intracellular neurofibrillary tangles. Both pathological processes disrupt neuronal function and promote cell death through distinct mechanisms.