Brain Disorders (Neurobiol Textbook) Flashcards
Pathologic hallmarks of Alzheimer’s disease
- Neurofibrillary tangles present within neurons, made up of Tau protein.
- Amyloid plaques throughout the cerebral cortex, made up of Aβ amyloid/protein fragments of amyloid precursor protein.
Note: Both of these may be present in normal aging brains as well, but in AD the extent of brain involved is much greater
Normal processing of APP
APP is normally cleaved to form Aβ via the proteolysis of two enzymes: β-secretase (N-terminal) and γ-secretase (C-terminal).
α-secretase, an enzyme which cleaves in the middle of Aβ peptide and thus prevents aggregation, was also discovered.
Different isoforms of Aβ exist depending upon where γ-secretase makes its cut – Aβ39, Aβ40, Aβ41, Aβ42, and Aβ43. Aβ40 and Aβ42 are the predominant forms. Of these, Aβ42 has a greater predilection for forming aggregates.
Origin of Alzheimer’s disease
Most cases are sporadic, however heritable mutations in APP and γ-secretase are also known to cause AD. Sporadic AD has an onset around age 65, while familial AD has a younger onset around age 40-50. All known causes of familial AD are autosomal dominant.
Mutations in APP associated with AD cluster in the Aβ region, specifically around secretase cleavage sites. Mutations that increase cleavage are associated with increased risk, while some mutations that decrease cleavage are actually associated with reduced risk.
APP and Down syndrome
APP is located on chromosome 21 – this patients with Down syndrome are at substantially increased risk of age-related mental degeneration and Alzheimer’s disease. This usually onsets around age 50.
Presenilins and Alzheimer’s disease
Presenilin-1 and presenilin-2, identified as being risk factors for Alzheimer’s disease, were found to be part of the γ-secretase signaling complex.
Aβ amyloid and Tau
The more amyloid is produced, the more Tau neurofibrillary tangles are also found. It has been suggested that formation of neurofibrillary tangles represents the ultimate pathology of Alzheimer’s disease, and that the plaques are only a possible step in this process.
Apo E and Alzheimer’s disease
Certain ApoE variants in the population are the widest spread risk factors for Alzheimer’s disease of all genes identified. ε3 is the most common variant of ApoE. Persons with ε4 are at increased risk of Alzheimer’s disease in a dose-dependent manner, with heterozygotes having a >3 fold risk of developing AD and homozygotes having a >12 fold risk of developing AD.
ApoE is a susceptibility locus, but unlike other genes (APP, presenilin), does not mean that an individual will develop Alzheimer’s disease if they live long enough.
The mechanism by which ApoE affects risk for AD is not well understood.
Microglia-regulating genes and Alzheimer’s disease
The most recent family of AD-regulating genes come from microglia.
TREM2, “triggering receptor expressed on myeloid cells-2”, is a receptor that facilitates phagocytosis in macrophages and microglia. Variants of TREM2 carry similar risk for AD compared to ApoE variants, but are much less common in the general population.
CD33, an inhibitory Siglec-family lectin expressed on macrophages and microglia, has also been associated with late-onset AD. CD33 has been shown to inhibit uptake of Aβ42 in-vitro, and mice lacking CD33 exhibit fewer Aβ plaques with age.
Major prion diseases
Scrapie - Found in sheep and goats who are exposed to infected tissiue
Kuru - Found in Papua New Guinea tribes where the consumption of human brain was performed as part of a religious ritual.
Creutzfeld-Jakob disease - Inherited or spontaneous mutation in prion protein.
All have hallmark pathology and are referred to as “spongiform encephalopathies”
Huntingtin
Mutated in Huntington’s disease with trinucleotide repeats near the N-terminus (CAG, resulting in serial glutamines). Normal Huntingtin has 6 to 34 glutamines, mutant huntingtin can have 36-121 repeats.
Spinocerebellar ataxia due to polyQ repeats
Just as with Huntingtin, polyQ expansions have been found to cause other forms of neurodegenerative disease, such as spinocerebellar ataxia. As with Huntington’s disease, the number of glutamines that distinguishes healthy vs diseased is around 35.
Pathology of PolyQ repeat proteins
From Huntington’s disease and SCA, it was hypothesized that polyQ repeat proteins themselves can aggregate to cause disease.
Indeed, polyQ repeats have been found to form aggregates in the nucleus, cytoplasm, or axon, depending upon which protein they are found in. These aggregates can still interact with the proteins that bind to the polyQ host protein, resulting in abnormal cellular signaling and regulation as well.
Thus, the cell of protein expression, location of inclusions, and the recruited proteins determine the range of symptoms in the PolyQ disorder.
Pathology of Amyotrophic lateral sclerosis
ALS results from familial (10%) or acquired (90%) mutations in SOD1, TDP-43, FUS, or C9orf72. In each case, mutant protein aggregates within motor neuron axons.
TDP-43 inclusions have been found in every case of ALS, irrespective of the gene of origin. Thus, it is thought that TDP-43 inclusion formation represents the convergent event of different pathologic pathways which cause ALS.
Shown are section from an unaffected individual (A) and ALS patient (B) stained for TDP-43.
Pathology of Parkinson’s disease
Loss of dopaminergic neurons in the substantia nigra pas compacta (SNc) results in loss of direct pathway stimulation via D1 and loss of indirect pathway inhibition via D2.
Thus, loss of these neurons ultimately decreases direct pathway activity and increases indirect pathway activity, resulting in excessive inhibitory signals toward the thalamus and brainstem targets.
Alpha synuclein
First identified as a gene in familial Parkinson’s disease, then in Lewy Body Dementia.
Lewy Bodies have been found to “spread” from cell to cell once established, with alpha synuclein behaving somewhat like a prion. Consistent with this, Lewy Bodies cannot spread in alpha synuclein knockout mice.
Metabolism of monoamines at the synapse
Resperine acts as an inhibitor of VMAT, preventing re-loading of monoamines into synaptic vesicles.
Drugs of abuse and the VTA
