Alzheimer’s DiseaseAlzheimer’s Disease

A Geriatric EpidemicA Geriatric Epidemic

Alzheimer’s DiseaseAlzheimer’s Disease

Alzheimer’s disease currently affects Alzheimer’s disease currently affects between two and four million Americans.between two and four million Americans.

Causes the degeneration of the nervous Causes the degeneration of the nervous system over timesystem over time

Two basic forms:Two basic forms:– Early onset (under 65)Early onset (under 65)– Late onset (65+)Late onset (65+)

HistoryHistoryThe first person to make a diagnosis of Alzheimer’s The first person to make a diagnosis of Alzheimer’s disease was Alois Alzheimer (1864-1915). Alzheimer disease was Alois Alzheimer (1864-1915). Alzheimer made the diagnosis on a fifty-one year old named made the diagnosis on a fifty-one year old named Frau Auguste D.Frau Auguste D.

A Belgian pathologist found amyloid to be a A Belgian pathologist found amyloid to be a component of the plaques found in the brains of component of the plaques found in the brains of those with Alzheimer’s in the 1930’s.those with Alzheimer’s in the 1930’s.

SymptomsSymptoms•Asking the same questions over and over again.

• Repeating the same story, word for word, again and again.

• Forgetting how to cook, or how to make repairs, or how to perform activities that were done with ease and regularity.

•Getting lost in familiar surroundings, or misplacing household items.

• Neglecting to complete everyday hygiene tasks.

•Relying on someone else to make easy decisions.

TreatmentTreatment

• The drug tacrine helps to slow the degeneration process, but it is costly and causes numerous side effects including the buildup of the toxic liver enzyme alanine aminotransferase.

• Like tacrine, other drugs can only delay the inevitable.

•To date there is no cure for Alzheimer’s disease.

Alzheimer’s PhysiologyAlzheimer’s Physiology

Alzheimer’s disease is characterized by Alzheimer’s disease is characterized by the presence of amyloid plaques and the presence of amyloid plaques and neurofibrillary tangles within the central neurofibrillary tangles within the central nervous system.nervous system.

The neurofibrillary tangles arrive as the The neurofibrillary tangles arrive as the result of defective tau proteins. result of defective tau proteins.

The plaques are derived from the buildup The plaques are derived from the buildup of β-amyloid protein, which in turn comes of β-amyloid protein, which in turn comes from amyloid precursor protein (APP). from amyloid precursor protein (APP).

Tau ProteinsTau Proteins

Healthy tau proteins help to support Healthy tau proteins help to support microtubules in neurons.microtubules in neurons.

Mutations on exon 10 on the mRNA strand Mutations on exon 10 on the mRNA strand coding for tau gives rise to 3 tau isoforms with coding for tau gives rise to 3 tau isoforms with four microtubule binding site instead of the usual four microtubule binding site instead of the usual three. three.

This interferes with the tau’s ability to interact This interferes with the tau’s ability to interact with the microtubule. Instead the free tau begins with the microtubule. Instead the free tau begins to interact with itself and begins building tangles.to interact with itself and begins building tangles.

Neurofibrillary Tangle FormationNeurofibrillary Tangle Formation

ββ-Amyloid Plaques-Amyloid Plaques

ββ-Amyloid is made from -Amyloid is made from post-translational amyloid post-translational amyloid precursor protein (APP).precursor protein (APP).Two different enzymatic Two different enzymatic pathways exist for APP.pathways exist for APP.Three different pathways Three different pathways exist for the site of APP exist for the site of APP digestion and the formation digestion and the formation of of ββ-amyloid.-amyloid.The formation of The formation of intracellular pools of intracellular pools of ββ--amyloid contributes to the amyloid contributes to the plaques characteristic of plaques characteristic of Alzheimer’s.Alzheimer’s.

Enzymatic PathwaysEnzymatic Pathways

-Aβ40 vs. Aβ42

Three Sites of APP DigestionThree Sites of APP Digestion

Mutations Contributing to PlaquesMutations Contributing to Plaques

Val717 mutation: increases ratio of Val717 mutation: increases ratio of Aβ42 to Aβ40

Swedish mutation: mutation of amino acid 670 Swedish mutation: mutation of amino acid 670 on APP from lysine to methionine along with on APP from lysine to methionine along with amino acid 671 going from asparagine to lysine; amino acid 671 going from asparagine to lysine; increases use of increases use of ββ-secretase pathway-secretase pathway

Presenilin mutation: increases ratio of Presenilin mutation: increases ratio of Aβ42 to Aβ40

Cell DeathCell Death

The Effect of Plaques on Action The Effect of Plaques on Action Potentials in the Nervous SystemPotentials in the Nervous System

Closing CommentsClosing Comments

Current research is looking to telomerase Current research is looking to telomerase for a possible cure for Alzheimer’s. for a possible cure for Alzheimer’s.

Pathologists also hope that stem cells may Pathologists also hope that stem cells may provide a cure.provide a cure.

Alzheimer’s not only affects the patients Alzheimer’s not only affects the patients but their families as well. It is a sad slow but their families as well. It is a sad slow course that leaves relatives emotionally course that leaves relatives emotionally exhausted.exhausted.

The EndThe End