The amyloid cascade hypothesis proposes that amyloid-beta protein (AβP) deposition in the brain is the primary cause of Alzheimer's disease (AD). AβP is produced when a larger amyloid precursor protein is cleaved by secretase enzymes. According to the hypothesis, AβP or its fragments trigger a cascade that results in neurofibrillary tangles, neural cell loss, and dementia. While evidence supports many aspects of the hypothesis, questions remain about whether AβP is the initial cause or a result of neurodegeneration in AD.

1. Alzheimer’s Disease: The
Amyloid Cascade
Hypothesis
J. A. Hardy and G. A. Higgins, “Alzheimer’s disease: the
amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp.
184–185, 1992.
A student seminar: Beshr Nammouz

2. Introduction: Alzheimer's Disease (AD):
- Causes dementia in many elderly people and in some individuals with Down Syndrome.
- Characterized by various pathological markers in the brain.

3. Pathological markers of AD:
- Large number of amyloid plaques, also called senile plaques (SPs).
- Surrounded by neurofibrillary tangles (NFTs).
- Vascular damage.
- Neural cell loss.

4. The hypothesis: Amyloid Beta protein (A𝛃P) deposition is the cause
of AD:
- AβP deposition (the main component of SPs) is the causative agent of: NFTs, cell loss,
vascular damage, dementia.

5. The A𝛃P:
- A peptide product by a larger amyloid precursor protein
(APP).
- 39- to 42-amino acid peptide.
- Starch-like.
- Forms insoluble extracellular deposits.
- APP gene undergoes alternative RNA splicing to
produce several protein isoforms.
- The predominant variant in brain lacks a serine protease
inhibitor domain that is present in APP molecules in
other tissues.

6. - APP is inserted into the cytoplasmic
membrane and then cleaved at residues
15 to 17 within the AβP sequence by the
APP secretase.
- This cleavage event produces fragments
that do not contain intact AβP and so
cannot result in amyloid deposition.
- These fragments include secreted NH2-
terminal derivatives that can be detected
in brain and cerebrospinal fluid.
How APP proteolysis leads to A𝛃P deposition:

7. - The APP secretase that cuts within the AβP region has an extraordinary broad sequence
specificity and recognizes the secondary structure of APP, cleaving at a defined distance
from the membrane.

8. - Several recent studies suggest that APP
can also be processed by the endosomal-
lysosomal pathway, after recycling of
membrane-bound APP and possibly via an
intracellular metabolic route.
- Carboxyl-terminal fragments containing the
entire AβP sequence can be derived from
this alternative normal processing of APP
and may eventually lead to amyloid
deposition.

9. - Mutations in the COOH-terminal portion of APP cause hereditary, early onset AD and
hereditary cerebral hemorrhage with amyloidosis (Dutch-type).
- The APP mutation that causes massive AβP deposition in the Dutch amyloidopathy is a
glutamic acid to glutamine substitution at codon 693 (in the longest APP form), located
only six residues away from the cleavage site within the AβP sequence.

10. - It has been speculated that this mutation might cause AβP deposition by inhibiting
secretase cleavage of APP. although this now seems less likely because of the apparent
lack of sequence specificity.
- Three mutations have been described within the APP gene that cause familial AD.
- These mutations all occur at codon 717 of the protein and change the native valine,
located three residues from the COOH-terminal end of AβP, to isoleucine, phenylalanine,
or glycine.
- It is unclear how these mutations cause amyloid deposition, but they may inhibit the
breakdown of a COOH-terminal fragment of APP that contains AβP, alter the anchoring
of APP in the cell membrane, or stabilize AβP-containing amyloidogenic fragments within
lysosomes.

11. Our cascade hypothesis states:
- That AβP itself, or APP cleavage products containing AβP, are neurotoxic and lead to
neurofibrillary tangle formation and cell death.
- Thus, two successive events are needed to produce Alzheimer's pathology:
a. AβP must be generated as an intact entity, either by accumulation of AβP or as an
AβP-containing fragment of APP.
b. This molecule must facilitate or cause neuronal death and NFT formation.

12. - Neve and her colleagues have reported that the AβP-containing COOH-terminal
fragment is toxic to culture neurons, and Kowall and co-workers have suggested that
AβP alone exerts toxic effects on neurons, an affected possibly mediated through the
serpin receptor.
- Other investigators, however, have reported that AβP itself is not a neurotoxic, but that it
renders neurons more sensitive to excitotoxic damage.
- Although it is not clear exactly how AβP causes neural loss and tangle formation, the
peptide is known to disrupt calcium homeostasis and increase intracellular calcium
concentrations.

13. - This observation could explain how NFTs form.
- NFTs are largely composed of paired helical filaments formed from a hyperphosphorylated
form of tau, and tau phosphorylation can be controlled by intracellular calcium.
- Thus, AβP may induce NFT formation as a consequence of its ability to increase intracellular
calcium, leading to phosphorylation of tau and the formation of paired helical filaments.
- The intervening steps by which AβP affects calcium homeostasis still remain to be elucidated.
- However the overall mechanism is consistent with what we know about calcium-mediated
neuronal death.

14. - The mutations in APP so far described are responsible only for a small proportion of
cases of AD.
- The cascade hypothesis suggests that other causes of AD act by initially triggering AβP
deposition, for example the association between head trauma and AD, and dementia
pugilistica and AD.
- The deposition could be caused by an induction of the APP gene through an interleukin-
mediated stress response because APP increases in response to number of neural
stresses.
- Although acute effects may only lead to transitory disruption of APP metabolism, it is
possible that in some individuals the entire pathological cascade leading to AD would be
initiated.

15. Conclusions:
- The evidence we have described supports the hypothesis that AβP molecule initiates
the pathological cascade of AD.
- AβP-containing COOH-terminal derivatives of APP seem the most likely molecular
candidates for initiation of the cascade.
- The ongoing development of transgenic animals that express APP or AβP and exhibit
Alzheimer's-like pathology should provide good models for experimental testing of key
elements in the cascade.
- The identification of additional mutations in APP and other genes that causes AD
pathology will allow refinement of amyloid cascade hypothesis and point to target for
therapeutic intervention.

16. Today:
- The amyloid cascade hypothesis has played the prominent role in explaining the
etiology and pathogenesis of AD.
- While there is substantial evidence supporting the hypothesis, there are also limitations:
a. SPs and NFTs may develop independently.
b. SPs and NFTs may be the products rather than the causes of neurodegeneration in
AD.
c. randomized clinical trials that tested drugs or antibodies targeting components of
the amyloid pathway have been inconclusive.

17. THANKS

18. - J. A. Hardy and G. A. Higgins, “Alzheimer’s disease: the amyloid cascade hypothesis,” Science, vol.
256, no. 5054, pp. 184–185, 1992.
- Medscape.
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