idle thoughts

BALL%YALEMED at PUCC.PRINCETON.EDU BALL%YALEMED at PUCC.PRINCETON.EDU
Sun Oct 14 11:29:00 EST 1990


Subscribers of the Biosci Ageing Bulletin Board:

     The following is a draft of AGE News, a publication of the
American Aging Association, 600 South 42nd Street, Omaha,
Nebraska 68198-4635.
                                   Sheldon Ball, editor AGE NEWS

Progress on Alzheimer's Disease

Amyloid

     The amyloid beta peptide (A4) is a 4.2 kD peptide that forms
the core of senile plaques in Alzheimer's disease.  The A4
peptide is derived from proteolytic processing of any one of 3
amyloid precursor proteins (APP) which, through alterative
splicing of trancripts from a single gene, are produced in at
least 4 different forms. (A secreted form of APP contains a
protease inhibitor domain but not a transmembrane domain or A4).
APP forms containing a Kunitz-type serine protease inhibitor
(KPI) domain (APP-770, APP-751 & APP-563) are found in a variety
of cell types not restricted to the brain, while APP-695, a form
which lacks the KPI domain, is restricted to the brain in its
distribution.  APP (isoforms not identified) is transported by
fast axonal transport to axon terminals (10).
     Platelets stimulated with thrombin secrete an inhibitor of
activated coagulation factor XIa. This inhibitor (XIa-I) has
been identified as a truncated form of APP that contains the KPI
domain and at least a portion of the amyloid beta peptide (1).
These findings suggest a possible role for APP in the regulation
of coagulation. Earlier studies have found that a truncated form
of APP containing a KPI domain, identified as protease nexin II,
is stored in alpha granules of platelets and released with other
granule constituents during activation by agents such as thrombin
or collagen (2). Protease nexin II is reported to have both
protease inhibitory and growth promoting activities suggesting
involvement in inflammatory responses and tissue repair.
     Embryonic human kidney 293 cells that had been stably
transfected with an expression vector coding for APP-751 mRNA
secrete a large (>100 kD), soluble, NH2-terminal APP fragment,
identified as protease nexin II, and generate an 11 kD membrane-
associated C-terminus (3). The protease catalyzing this cleavage
is termed APP secretase. Direct microsequencing indicated that
APP cleavage by the secretase occurs in the middle of the A4
sequence, precluding APP secretase activity as a step in the
formation of A4. Similar results were obtained with cells
transfected with an expression vector coding for APP-695 mRNA.
The authors suggest that abberant processing of APP, perhaps
secondary to inhibition of APP secretase, may be involved in the
formation of A4 in patients with Alzheimer's disease.
     A candidate for such aberrant processing of APP is clipsin
or some protease related to clipsin (11). Clipsin is a membrane-
associated chymotrypsin-like protease of Mr 25 kD irreversibly
inhibited by alpha-1-antichymotrypsin, a protease inhibitor
identified as an integral component of neuritic plaques. The
alpha-1-antichymotrypsin is produced by astrocytes (12). Clipsin
was found to cleave synthetic peptides succinyl-Ala-Ala-Pro-Phe-
p-nitroanilide and methoxy-succinyl-Ala-Ala-Pro-Met-p-
nitroanilide, the latter being of significance because cleavage
after a methionine residue is predicted to generate the amino
terminus of the A4 peptide.
     Quantitative in situ hybridization studies of mRNAs of
specific APP transcripts have provided some clues to the etiology
of senile plaques in Alzheimer's disease.   Higgins et al (4)
used this technique to demonstrate increased KPI containing APP
transcripts (APP-751, APP-770 & APP-563) relative to APP-695
transcripts (which does not contain the KPI motif) in the basal
forebrain of aged rats. The increase was found to be specific to
animals who exhibited spatial memory deficits but not aged rats
without behavioral impairments. Johnson et al (5) reported an
increase in APP-751/APP-695 mRNA in cortex and hippocampus but
not cerebellum in Alzheimer's disease patients. In situ
hybridization on serial sections indicated that hippocampal
pyramidal neurons contain both APP-751 and APP-695 mRNA. A
relationship between the increase in APP-751/APP-695 mRNA ratio
in pyramidal neurons and the density of plaques in the
hippocampus and entorhinal cortex (input to hippocampus) was
found.  The implications of these findings for the pathogenesis
of Alzheimer's disease are not clear since amyloid plaques are
not found in the brains of aged rats; however, there may be
implications for the role of proteases and their inhibitors in
the neuropathology of the aging brain.

Acetylcholine

     Loss of cholinergic neurons in the basal forebrain is a
frequent if not consistent autopsy finding in Alzheimer's disease
patients. Cholinergic neurons in the nucleus basalis, one of the
basal forebrain nuclei, project diffusely to the cerebral cortex.
Consistent with the loss of cholinergic projections, cerebral
cortical areas involved in Alzheimer's disease were found at
autopsy to exhibit diminished acetylcholine transferase activity
(6). Remaining cholinergic terminals displayed marked up-
regulation of high affinity [3H]choline uptake. As choline uptake
is rate limiting in cortical acetylcholine biosynthesis, these
findings underscore the significance of the loss of cholinergic
projections and the compensatory hyperactivity of remaining
cholinergic terminals in cerebral cortex of Alzheimer's disease
patients.

Circadian Rhythms

     The suprachiasmatic nucleus in the hypothalamus is
considered to be the endogenous circadian clock in the mammalian
brain. This nucleus shows morphological changes with aging, which
become even more pronounced in Alzheimer's Disease. Wittig et al
(7) find no difference in circadian rest-activity rhythms in a
small group of young and old volunteers, yet find marked
disturbances in Alzheimer's disease patients which tended to
correlate with severity of the dementia. Circadian disturbances
were most pronounced in patients medicated with sedatives
although no differences were found before and after
administration of medication. Disturbances in circadian rhythms
and sleep patterns have also been noted in aged rats and young
rats with lesions in the basal forebrain cholinergic system and
these have also been correlated with poor performance in memory
tasks (8,9).

1. Smith RP; Higuchi DA; Broze GJ Jr (1990) Platelet coagulation
factor XIa-Inhibitor, a form of Alzheimer amyloid precursor
protein. Science 248:1126-28

2. Selkoe DJ (1990) Deciphering Alzheimer's disease: The amyloid
precursor protein yields new clues. Science 248:1058-60

3. Esch FS; Keim PS; Beattle EC; Blacher RW; Culwell AR;
Oltersdorf T; McClure D; Ward PJ (1990) Cleavage of amyloid beta
peptide during constitutive processing of its precursor. Science
248:1122-24

4. Higgins GA; Oyler GA; Neve RL; Chen KS; Gage FH (1990) Altered
levels of amyloid precursor transcripts in the basal forebrain of
behaviorally impaired aged rats. Proc Natl Acad Sci USA 87:3032-
36

5. Johnson SA; McNeill T; Cordell B; Finch CE (1990) Relation of
APP-751/APP-695 mRNA ratio and neuritic plaque density in
Alzheimer's disease. Science 248:854-57

6. Slotkin TA; Seider FJ; Crain BJ; Bell JM; Bissette G; Nemeroff
CB (1990) Regulatory changes in presynaptic cholinergic function
assessed in rapid autopsy material from patients with Alzheimer's
disease: implications for etiology and therapy. Proc Natl Acad
Sci USA 87:2452-55

7. Wittig W; Kwa IH; Eikelenboom P; Mirmiran M; Swaab DF (1990)
Alterations in the circadian rest-activity rhythm in aging and
Alzheimer's disease. Biol Psychiatry 27:563-72

8. Stone WS (1989) Sleep and aging in animals: Relationships with
circadian rhythms and memory. Clinics in Geriatric Medicine,
5:363-79

9. Stone WS; Altman HJ; Berman RF; Caldwell DF; Kilbey MM (1989)
Association of sleep patterns and memory in intact old and
nucleus basalis-lesioned young rats. Behav Neurosci 103:755-64

10. Koo EH; Sisodia SS; Archer DR; Martin LJ; Weidemann A;
Beyreuther K; Fischer P; Masters CL; Price DL (1990) Precursor of
amyloid protein in Alzheimer disease undergoes fast anterograde
axonal transport. Proc Natl Acad Sci USA 87:1561-1565

11. Nelson BB; Siman R (1990) Clipsin, a chymotrypsin-like
protease in rat brain which is irreversibly inhibited by alpha-1
antichymotrypsin. J Biol Chem 265:3836-3843

12. Abraham CR; Shirahama T; Potter H (1990) Alpha 1-
antichymotrysin is associated solely with amyloid deposits
containing the beta-protein. Amyloid and cell localization of
alpha 1-antichymostrypsin. Neurobiol Aging 11:123-129

Cellular Senesence

     The shortening of telomeres during passage of human
fibroblasts in vitro has prompted speculation that this
phenomenon may play a role in human aging (1). Kipling and Cooke
(2) now report that the mouse genome contains 8-16 times more
telomeric DNA (TTAGGG repeats in all vertebrates) than the human
genome and that the mouse telomeres are not significantly reduced
in size during the animal's lifespan.  Mouse telomeres seem to
differ from human telomeres in being highly polymorphic in
length, possibly a result of germ line mosaicism. No difference
in mouse telomeric DNA from liver, brain, spleen, or testes is
apparent. Telomeric DNA from human peripheral blood cells is 10
kb, from human fibroblasts 7 kb, and from human sperm 9 kb. Mouse
telomeric DNA varies from 25-150 kb.
     Human endothelial cells, like human fibroblasts, have
limited proliferative capacity in vitro. It seems now, that
interleukin-1 (IL-1) alpha may play a role in regulation of
endothelial cell senescence (3).  Senecent human endothelial
cells contain relatively large amounts of transcripts for the
cytokine IL-1 alpha, a potent inhibitor of endothelial cell
proliferation.  In contrast, transformed human endothelial cells
do not contain detectable amounts of IL-1 alpha mRNA.  Treatment
of human endothelial cells with an anitisense
oligodeoxynucleotide to the human IL-1 alpha prevented cellular
senescence and extented the proliferative lifespan of the cells
in vitro. Removal of the IL-1 alpha antisense oligomer resulted
in generation of the senescent phenotype and loss of
proliferative potential. The authors suggest that human
endothelial cell senescence in vitro is a dynamic process
regulated by IL-1 alpha.

1. Harley, CB; Futcher, AB; Greider CW (1990) Telomeres shorten
during ageing of human fibroblasts. Nature 345:458-460

2. Kipling D; Cooke HJ (1990) Hypervariable ultra-long telomeres
in mice. Nature 347:400-402

3. Maier, JAM; Voulalas, P; Roeder, D; Maciag, T (1990) Extension
of the life-span of human endothelial cells by interleukin-1
alpha antisense oligomer. Science 249:1570-1574.

Transcendental Meditation, Mindfulness, and Longevity

     Can direct change in the state of consciousness through
specific mental techniques extend human life and reverse the age-
related declines? To address this question, Alexander et al (1)
randomly assigned 73 elderly individuals (mean age 81 years)
amoung four groups; a no treatment group and three groups with
treatments highly similar in external structure and expectations:
1) the Transcendental Meditation (TM) program; 2) mindfulness
training (MF) in active distinction making; 3) a relaxation (low
mindfulness) program. A comparison on paired associate learning,
two measures of cognitive flexibility, mental health, systolic
blood pressure, and ratings of behavioral flexibility, aging, and
treatment efficacy indicated that the TM group improved the most,
followed by MF, in contrast to relaxation and no-treatment
groups. The MF group improved most, followed by TM, on perceived
control and word fluency. After three years, survival rate was
100% for TM and 87% for MF in contrast to lower rates for the
other two groups.

1. Alexander CN; Langer EJ; Newman RI; Chandler HM; Davies JL
(1990) Transcendental meditation, mindfulness, and longevity: and
experimental study in the elderly. J Pers Soc Psychol 57:950-64





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