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UNIVERSITY OF NIGERIA, NSUKKA

FACULTY OF BIOLOGICAL SCIENCES


DEPARTMENT OF BIOCHEMISTRY
SPECIAL TOPICS IN MEDICAL BIOCHEMISTRY I (BCH 522)

THE GENETICS OF ALZHEIMER ‘S DISEASE(AD)

NAME: AYOLOTU MUYIWA AUGUSTINE


REG NUMBER: PG/M.Sc/13/66634

SUPERVISORS:
PROF. F.C. CHILAKA / DR. S.O.O. EZE
INTRODUCTION
 Protein molecules are responsible for almost all biological functions in cells. In order to fulfil their various
biological roles, these chain-like molecules must fold into precise three-dimensional structure.

 In the cell, most proteins require assistance for proper folding by ‘molecular chaperones’. These are specialized
proteins which protect, not-yet folded proteins from misfolding and clumping together (aggregating).

 Inability for the molecular chaperones to guide the integrity of these proteins eventually leads to misfolding and
aggregation which in turn lead to a diseased state.
Why is protein misfolding and aggregation such an important problem?
The reasons are of two-fold:

1. LOSS OF FUNCTION: When a protein fails to fold correctly upon synthesis or misfolds at a later stage in
its cellular life time, it can no longer fulfill its biological function. This may happen as a result of
inherited mutations in proteins, which cause a change in the amino acid sequence. E.g cystic fibrosis,
tumor suppressor protein p53.

2. TOXICITY: Their is probably more critical danger arising from aberrant folding which lies in the fact that
misfolded and aggregated proteins are toxic to cells, apparently because their accumulation interferes
with a variety of cell functions. This insight provides the basis for many age-related diseases of the
nervous system, such as Alzheimer’s disease and other neurodegenerative disorders .
Figure 1: Overview of the possible fates of a newly synthesized polypeptide chain.
Source: Stefani, M. and Dobson, C.M. (2003).
ALZHEIMER’S DISEASE(AD)
 AD was first described by Alois Alzheimer in 1906 , by analyzing two stains section from Augustine Deter’s brain
(Alzheimer’s first patient).

 AD is an irreversible, progressive neurodegenerative disorder characterized by the presence of lesions both at an


extracellular level (the b-amyloid plaques), and at an intracellular levels (the Neurofibrillary tangles, NFT).

 This neuropathological hallmark for the disease correlates with both reduction in the volume of the brain (as a
consequence of the neurodegenerative phenomena), and with cognitive decline associated to loss of memory.

Alois Alzheimer Augustine Deter’s


(1864-1915) Alzheimer’s first patient
TYPES OF ALZHEIMER’S DISEASE
There are three known types of Alzheimer’s disease. They include:

 Early-onset AD: This is a rare form of Alzheimer's disease in which people are diagnosed with the disease
before age 65. Less than 10% of all Alzheimer's disease patients have this type. Because they experience
premature aging, people with Down syndrome are particularly at risk for a form of early onset Alzheimer's
disease. Adults with Down syndrome are often in their mid- to late 40s or early 50s when symptoms first
appear. Younger people who develop Alzheimer's disease have more of the brain abnormalities that are
associated with it. Early-onset Alzheimer's appears to be linked with a genetic defect on chromosome 14, to
which late-onset Alzheimer's is not linked. A condition called myoclonus -- a form of muscle twitching and
spasm -- is also more commonly seen in early-onset Alzheimer's than in late-onset Alzheimer's.

 Late-onset AD: This is the most common form of Alzheimer's disease, accounting for about 90% of cases, and
usually occurs after age 65. Late-onset Alzheimer's disease strikes almost half of all people over the age of 85
and may or may not be hereditary. Late-onset dementia is also called sporadic Alzheimer's disease.

 Familial AD (FAD). This is a form of Alzheimer's disease that is known to be entirely inherited. In affected
families, members of at least two generations have had Alzheimer's disease. FAD is extremely rare,
accounting for less than 1% of all cases of Alzheimer's disease. It has a much earlier onset (often in the 40s).
PET MRI

Normal

AD

Figure 2: ANATOMY OF THE ALZHEIMER’S DISEASE BRAIN.


Source: Mahesh and Shazia, 2014
Figure 3: BRAIN CROSS-SECTIONS OF BOTH NORMAL AND ALZHEIMER’S.
Source: Fall, 2010.
NEUROPATHOLOGY AND BIOCHEMISTRY OF AD

 Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral


cortex and certain subcortical regions.
 This loss results in degeneration in the temporal lobe and parietal lobe, and parts of
the frontal cortex.
 Reductions in the size of specific brain regions in patients as they progressed from
mild cognitive impairment to Alzheimer's disease
 Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The
beta-amyloid fragment is crucial in the formation of senile plaques in AD.
 Plaques are made up of small peptides, 39–43 amino acids, called beta-amyloid (also
written as a-beta or aβ).
Fragment from a larger protein called APP, a transmembrane protein that
penetrates through the neuron's membrane.
 In Alzheimer's disease, an abnormal aggregation of the tau protein lead to the
disintegration of microtubules in brain cells.
 Tau protein(microtubule-associated protein) stabilizes the microtubules when
phosphorylated.
 In AD, tau becoming hyperphosphorylated; creating neurofibrillary tangles and
disintegrating the neuron's transport system.
RISK FACTORS OF ALZHEIMER’S DISEASE
The major risk factors of AD are;

1. Ageing

2. Hereditary
 Amyloid Precursor proteins (APP)
 Members of the secretase complex, like Presenilin 1 (PS1) and Presenilin 2
(PS2)
 ApoE e4 allele polymorphism

3. Environmental Factor such as


 head injuries
 hormonal changes
 vascular diseases
 inflammation
 exposure to metals, like Cu++ and Zn++
AGEING
 This is the major risk factor of the late-onset type of AD.
 Ageing is not adaptation or genetically programmed perhaps by biological timetable
which regulate growth and development. There are two of the various theories of
ageing that fully support the risk factor of ageing leading to AD:
1. Immunological theory stipulates that the immune system is programmed to
decline over time which leads to increased vulnerability to infectious diseases and
then death.
2. Cross-linking theory which states that accumulation of cross-linked proteins
damages cells and tissues, slowing down bodily process.
 Telomerase theory could also be linked to this. Due to inadequate amount of
telomerase in the stem cells, the cell shortens as it divides and with time this could
lead to AD
 This stage of disease is sporadic and is the common form of dementia accounting for
over 60% of the population of Alzheimic patients.
 Dementia is the loss of intellectual functions (such as thinking, remembering, and
reasoning) of sufficient severity to interfere with a person’s daily functioning.
Genetics of AD
 Depending on the kind of mutation and on the gene that carries it, the onset of the
disease is SIGNIFICANTLY EARLIER than in sporadic cases (before 65 years of age).

 All the mutations are autosomal dominant, and involve :APP protein, Members of the g-
secretase complex, like Presenilin 1 (PS1) and Presenilin 2 (PS2) and ApoE e4 allele
polymorphism

AMYLOID PRECURSOR PROTEINS(APP)


 Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a
transmembrane protein that penetrates through the neuron's membrane.
 APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an
unknown process causes APP to be divided into smaller fragments by enzymes through
proteolysis.
 One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that
deposit outside neurons in dense formations known as senile plaques.
When APP is cleaved by β- and γ-
secretase enzymes, neurotoxic Aβ
peptides are released, which can
accumulate into oligomer
aggregates.
Small size allows them to diffuse
into the synapse, impairing
synaptic function between
neurons.
Aggregate into insoluble β-sheet
amyloid fibrils, which can trigger a
local inflammatory response,
leading to oxidative stress and
biochemical changes which cause
death of neurons and
development of plaques
Figure 4: AMYLIOGENIC PROCESSING OF APP.
Source: Patterson C. et al., 2008
Mutations on APP
 Chromosome 21. Relation to Down’s syndrome (Trisomy 21; excess of APP transcript induces plaque
formation already at early age, and progresses with aging).

 Swedish mutation: K(Lys)670M(Met)/N(Asn)671L(Leu), facilitates the amyloidogenic processing of APP by


increasing the affinity for and the cleavage by b-secretase of ~100 times.
 Dutch Mutation: E(Glu)693Q(Gln), induces cerebral amyloidosis
 Arctic Mutation:E(Glu)693G(Gly) enhances b-Amyloid protofibril formation
 London Mutation: V(Val)717I(Iso), Affects the cleavage of g-secretase

K670M/N671L
E693G V717I
Swedish Mutation Arctic Mutation London Mutation
AMYLOID PRECURSOR PROTEINS (APP) CONT’D
 AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an
internal support structure partly made up of structures called microtubules.
 These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon
and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-
associated protein.
 In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads,
creating neurofibrillary tangles and disintegrating the neuron's transport system.

Figure 5: Tau’s Mechanism of Action.


Source: Ballatore, C., et al., (2007).
Mutations on Presenilins
PS1 (on chromosome 14) PS2 (on chromosome 1) are ~450 aa long aspartyl proteases comprised of 7- to 8-
transmembrane spanning domains. They are the catalytic part of a tetrameric protein complex called g-secretase, able to
cleave APP at the end of the sequence for b-Amyloid peptides, generating b-Amyloid species.

More than 70 mutations on PS1 gene account for inherited AD.

Two mutations on PS2 gene account for inherited AD.

Figure 1: Overview of PS1 mutations and APP


Source: Hardy and Selkoe, 2002
APOLIPOPROTEIN E (APOE)

Apolipoprotein E (APOE) found on chromosome 19 appears to be a predisposing genetic


risk factor for the late on-set of AD the most typical AD.
APOE helps carry cholesterol in the bloodstream.
APOE comes in several different forms, or alleles.
Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
SYMPTOMS IN AD
 Increasing and persistent forgetfulness

 Difficulty performing familiar tasks

 Problems with finding the right words to express your thoughts

 Disorientation with time and place

 Poor or impaired judgment

 Problems with abstract thinking

 Putting everyday items in illogical places

 Mood, behavior or personality changes.


THE 2011 NIA (NATIONAL INSTITUTE OF AGING)- ALZHEIMER’S ASSOCIATION
DIAGNOSTIC CRITERIA 14
The pathological mechanisms are classified into 3 stages:
1. Pre-clinical Alzheimer’s disease-Newly defined stage which reflects the current evidence that biomarker changes in the
brain may occur before symptoms affecting the cognitive, non cognitive & functional abilities.
2. Mild cognitive impairment (MCI) due to Alzheimer's disease- More research is needed to distinguish those with MCI who
will go on to develop Alzheimer’s dementia from those who will not. Biomarkers, as they become validated, may help
increase diagnostic accuracy in research settings.
3. Dementia due to Alzheimer’s Disease- Emphasized the need for ruling out other causes of cognitive decline &
documenting progressive decline over time. The diagnosis of Alzheimer’s dementia may not always have memory
impairment as its most central characteristic; a decline in other aspects of cognition (such as word-finding, vision/spatial
issues, and impaired reasoning, judgment, and problem solving) may be the presenting or most prominent symptoms at
first. For research, diagnostic certainty may be improved by incorporation of certain biomarker measures. The 2013 DSM-V
(Diagnostic and Statistical Manual of Mental disorders, 5th edition.) criteria for Alzheimer’s and Dementia15
•The term Dementia is replaced with neuro-cognitive disorder and mild neuro cognitive disorder which focussed on decline
rather than deficit in function.
•Biological markers for Alzheimer’s disease appear well before the onset of symptoms such as memory problems and
functional impairment.
•The combination of symptoms and biomarkers (Aβ, Τau) support significantly that mild neurocognitive disorder will
progress to major neurocognitive disorder. Sensitive & specific biomarkers are yet to be identified for most of the
neurocognitive disorders.
DIFFRENTIAL DIAGNOSIS
The two major biomarkers which aids in the diagnosis of Alzheimer’s disease include Aβ protein (Amyloid beta)
and T protein (Tau).
Biomarkers of Aβ accumulation-
•Abnormal retention of beta-amyloid identifying tracer compounds on positron emission tomography (PET)
imaging.
•Low levels of beta-amyloid 1-42 in cerebrospinal fluid (CSF).

Biomarkers of Tau accumulation-


•Elevated levels of the protein tau (both total and phosphorylated tau) in CSF.
•Decreased fluorodeoxyglucose 18F (FDG) uptake on PET imaging in a specific pattern involving the brain’s
temporo-parietal cortex.
Atrophy on structural magnetic resonance imaging (MRI), again in a specific topographic pattern involving the
brain’s medial, basal &lateral temporal lobes and medial - lateral parietal cortices.
PREVENTION AND MANAGEMENT
 Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging
advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.

 In vitro, N-methylated AB(16-20)m peptides can prevent the aggregation of full length AB peptide and also disassemble
existing fibrils and possibly small oligomers as shown below

16K(me)LV(me)FF

Aβ40: DAEFRHDSGYEVHHQ16KLVFFA22EDVGSNKGAIIGLMVGGVV

 Cholinesterase inhibitors increase the levels of acetylcholine in the brain, which plays a key role in memory and learning.
This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it.
Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil
HCL), Exelon (rivastigmine), and Razadyne (galantamine).

Meredith and co-workers, J. Pep. Res. (2002) 60, 37-55


Current Immunotherapy for Alzheimer's Disease
The administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive
vaccination) stimulates Aβ clearance from the Alzheimer's disease brain and represents the
most innovative approach of anti-Alzheimer's disease therapy. However, an active anti-Aβ
vaccine (AN1792) has been discontinued because it caused meningoencephalitis in 6% of
Alzheimer's disease patients treated. Among passive immunotherapeutics, two Phase III
clinical trials in mild-to-moderate Alzheimer's disease patients with bapineuzumab, a
humanized monoclonal antibody directed at the N-terminal sequence of Aβ, were
disappointing. Another antibody, solanezumab, directed at the mid-region of Aβ, failed in two
Phase III clinical trials in mild-to-moderate Alzheimer's disease patients. A third Phase III study
with solanezumab is ongoing in mildly affected Alzheimer's disease patients based on
encouraging results in this subgroup of patients. Second-generation active Aβ vaccines (ACC-
001, CAD106, and Affitope AD02) and new passive anti-Aβ immunotherapies (gantenerumab
and crenezumab) are being tested in prodromal Alzheimer's disease patients, in
presymptomatic individuals with Alzheimer's disease-related mutations, or in asymptomatic
individuals at risk of developing Alzheimer's disease to definitely test the Aβ cascade
hypothesis of Alzheimer's disease.
CONCLUSION

The relationship between Aβ protein and Tau Protein is still little understood.
Scientific research is essential in answering all related questions.
AD is better known in its complexity and new avenues raise real hope for the eradication of
this devastating disease.