The PPT entitled "Pathophysiology of Alzeimer's Disease" basically gives an insight of the pathogenesis mechanism involved in AD, highlighting the mechanism of formation of Neuritic Plaques and Neurofibrillary tangles which are found to be the hallmark lesions of AD . The PPT is made simple and the information provided is from authentic resources.
2. Introduction
• Alzheimer’s disease is a degenerative brain disorder of unknown
etiology, which is the most common form of dementia, that usually
starts in late middle age or in old age, results in progressive memory
loss, impaired thinking, disorientation, and changes in brain neurons
especially in the cerebral cortex and presence of neurofibrillary tangles
and plaques containing beta-amyloid cells
Meaning: Alzheimer’s disease is a chronic, irreversible disease that
affects the cells of the brain and causes impairment of intellectual
functioning, which gradually destroys the ability to reason, remember,
imagine, and learn.
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3. Origin of Alzheimer’s Disease:
• The disease was first described by Dr. Alois Alzheimer, a German
physician, in 1906. Alzheimer had a patient named Auguste D, in her
fifties who suffered from what seemed to be a mental illness. But
when she died in 1906, an autopsy revealed dense deposits, now called
neuritic plaques, outside and around the nerve cells in her brain. Inside
the cells were twisted strands of fibre, or neurofibrillary tangles. Since
Dr. Alois Alzheimer’s was the first person who discovered the disease,
AD was named after him
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4. Comparison of a normal aged brain(left) and an
Alzheimer’s patient’s brain(right). Differential
characteristics are pointed out
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5. Features of AD
• Grossly, the brain is often reduced in weight and bilaterally atrophic.
• Microscopically, the main features are as under:
i) Senile neuritic plaque is the most conspicuous lesion and consists of
focal area which has a central core containing Aβ amyloid.
ii) Neurofibrillary tangle is a filamentous collection of neurofilaments
and neurotubules within the cytoplasm of neurons.
iii) Amyloid angiopathy is deposition of the same amyloid in the vessel
wall which is deposited in the amyloid core of the plaque.
iv) Granulovacuolar degeneration is presence of multiple, small
intraneuronal cytoplasmic vacuoles, some of which contain one or more
dark granules called Hirano bodies
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6. Hallmarks in AD
• Neuritic plaques are are focal, spherical collections of dilated,
tortuous, neuritic processes (dystrophic neurites) often around a
central amyloid core, which may be surrounded by a clear halo (Fig.
28-38A). They range in size from 20 to 200 µm in diameter;
microglial cells and reactive astrocytes are present at their
periphery.extracellular deposits of amyloid beta in grey matter
(neocortex, hippocampus, amyglada, less commonly basal ganglia and
elsewhere) of the brain
• Neurofibrilary tangles (NFT) are tau-containing bundles of filaments
in the cytoplasm of the neurons that displace or encircle the nucleus
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7. •Several mechanisms involved in pathogenesis of
AD:
I. βAP aggregation & deposition plaque
formation
II. Hyperphosphorylation of Tau protein
NFT development
III. Inflammatory processes
IV. Other genetic risk factors
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9. I.Role of Aβ-Neuritic Plaques
Amyloid precursor protein (APP) is a cell surface protein with a single
transmembrane domain that may function as a receptor, possibly for
prion protein (PrPc) among other ligands.
The Aβ portion of the protein extends from the extracellular region into
the transmembrane domain as shown in the fig from previous slide.
Processing of APP begins with cleavage in the extracellular domain,
followed by an intramembranous cleavage.
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10. There are two potential pathways, determined by the type of initial
proteolytic event.
If the first cut occurs at the α secretase
site within the Aβ sequence, then Aβ is
not generated (the nonamyloidogenic
pathway).
Surface APP can also be endocytosed and may
undergo cleavage by βsecretase, which cuts at the
Nterminal region of the Aβ sequence (the
amyloidogenic pathway).
Following cleavage of APP at either of these
sites, the γ-secretase complex performs an
intramembranous cleavage
Following cleavage of APP at
either of these sites, the γ-
secretase complex performs an
intramembranous cleavage
Pairing of α secretase +
𝜸𝑠ecreatase Soluble fragment is formed
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11. Pairing of β-secretase + γ-secretase cleavage, it generates Aβ
Once generated, Aβ is highly prone to aggregation—first into small
oligomers (which may be the toxic form responsible for neuronal
dysfunction), and eventually into large aggregates and fibrils.
(the amyloidogenic
pathway)
Point mutations in APP are another cause of familial
AD. Some mutations lie near the βsecretase and γ-
secretase cleavage sites, and others sit in the Aβ
sequence and increase its propensity to aggregate.
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12. These mutations lead to a gain of function,
such that the γ-secretase complex generates
increased amounts of Aβ, particularly Aβ42
These clusters form larger deposits called
Amyloid Plaques/Neuritic Plaques
Neurodegeneration
Neuronal loss AD
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13. II.Role of tau-Neurofibrillary tangles
Tau is a microtubule associated protein present in axons in association with the
microtubular network.
Abnormal Phosphorylation
(Hyperphosphorylation)of tau protein
These pathologically modified Tau
molecules perturb MT(Microtubule)
function
Fibrillation and Aggregation
Neurofibrillary tangles AD
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14. III. Role of Inflammation
Both small aggregates and larger deposits of Aβ elicit an
inflammatory response from microglia and astrocytes.
This response probably assists in the clearance of the
aggregated peptide, but may also stimulate the secretion of
mediators that cause damage
Additional consequences of the activation of these
inflammatory cascades may include alterations in tau
phosphorylation, along with oxidative injury to the
neurons
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15. IV.Other genetic risk factors
The genetic locus on chromosome 19 that encodes apolipoprotein
E (ApoE) has a strong influence on the risk of developing AD
Three alleles exist (ε2, ε3, and ε4) based on two amino acid
polymorphisms
The dosage of the ε4 allele increases the risk of AD and
lowers the age of onset of the disease, such that individuals
with the ε4 allele are overrepresented in populations of
patients with AD
This ApoE isoform promotes Aβ generation and
deposition, although the mechanisms have not been
established
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16. • Overall, this locus has been estimated to convey about a quarter of the
risk for development of lateonset AD.
• Genomewide association studies have identified several other loci that
contribute to the risk of AD.
• The connection between these genetic loci and the pathogenesis of AD
remains to be explored.
References:
-Robbins and Cotran Pathologic Basis of Disease.
-Barbier P, Zejneli O, Martinho M, Lasora A, Belle V,Smet-Nocca C,
Tsvetkov PO,Devred F and Landrieu I(2019) Role of Tau as a
Microtubule-Association Protein:Structural and Functional aspects.
Front. Aging Neurosci.11:204. doi:10.3389/fnagi.2019.00204
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